Overview, History, Essential Concepts, and Current Topics in Transplant Immunology

Biology, Medicine / By
First Author: Anahita Kodali1

Co-Authors: Vaishavi Agrawal2, Vivek Babu3, Sakeena Badrane2, Olivia Brado4, Sanah Handu2, Akshay Kelshiker1

1Dartmouth College, 2University of Pittsburgh, 3Drexel University, 4Trinity College
Overview, History, Essential Concepts, and Current Topics in Transplant Immunology

Figure 1: The Saints Cosmas and Damien, pictured above, were Arab physicians who practiced around the third century, A. D. They are renowned as the patron saints of surgery; in one fabled tale, the two were able to cure a dying patient by amputating a cancerous leg and transplanting a new one (Androutsos et. al., 2008). Their work sparked a centuries-long investigation into transplants, a field of study that continues today.

Source: Wikimedia Commons

In an increasingly technologically advanced society, the extent to which scientific developments have an impact in the practice of modern medicine can be overlooked; one significant advancement of modern medicine has been the widespread use of transplantation. Transplantation has only been widely successful within the last 60 years, although there are recorded attempts of this practice as early as the second century (Barker & Markmann, 2013). A transplant, by definition, refers to an organ, tissue or some other foreign entity being removed from its original location and placed in a new one. Often, organs are transplanted from one individual to another in order to rectify a deficiency or abnormality in the original organ. When successful, this procedure is very effective in allowing the recipient to continue living a normal life with minimal complications. Now, transplants are a standard medical procedure (“About Transplantation,” n. d.).

Transplant Background

In order to begin with a transplantation procedure, an appropriate donor organ must first be matched with the recipient, a process critical to minimizing the chances of allograft rejection; allografts refer to tissue grafts from the same species as the recipient that have a different genetic makeup (“Organ Transplantation”, 2020). This process entails ensuring that the proteins (otherwise known as antigens) on the surface of the donor organ are as similar as possible to the antigens on the recipient’s own organs. No match is perfect (unless the donor and the recipient are identical twins), but there are immunosuppressive drugs that can be used to reduce the possibility of rejection as much as possible (“Transplant Rejection”, Penn State Milton S. Hershey Medical Center, 2019).

Once a donor organ has been identified, a surgery is performed to transplant the organ into an individual that needs it (“Organ Transplantation”, 2020). After the procedure is completed, close monitoring of the patient’s state begins in order to look for signs of organ rejection. While symptoms characterizing rejection can vary depending on the organ transplanted, common symptoms include elevated temperature and swelling in the area around the transplanted organ (“Transplant Rejection,” UVA Health, n. d.). Exams and tests may also be performed to more accurately detect if rejection is occurring. For example, a biopsy, the extraction and examination of patient cells, can confirm rejection even before the rejection manifests itself in noticeable physiological symptoms, but is usually only done after multiple other tests have already been performed. Whether or not the individual displays symptoms of rejection, however, immunosuppressive drugs will most likely be prescribed or given to the individual in order to mitigate the chances of organ rejection; organ rejection, if left untreated, is fatal. Consistent and careful monitoring will most likely be required as well in the upcoming months to ensure that there are no further complications. The individual will be encouraged to contact a medical professional if he or she starts to experience characteristic symptoms of organ rejection or any kind of discomfort (“Transplant Rejection”, Penn State Milton S. Hershey Medical Center, 2019).

There are a number of reasons a transplant may be rejected from an individual’s body. The immune system is specifically designed to detect and destroy any foreign substances that enter the body, which leads to significant complications when trying to transplant foreign tissue. (“Transplant rejection,” MedlinePlus Medical Encyclopedia, n. d.). A transplant can undergo one of three types of failure: hyperacute, acute, or chronic.

Hyperacute transplant failure occurs within a few minutes of the transplantation procedure being completed when the antigens are immediately recognized as foreign by the body’s immune system. In this case, the organ or tissue must be removed immediately to prevent a severe reaction (“Transplant rejection,” MedlinePlus Medical Encyclopedia, n. d.). Hyperacute transplant failure is fairly rare today because the DNA matching, antigen analysis, and other forms of examination ensure that such an obvious rejection will likely not occur (“Understanding Transplant Rejection,” n. d.).

Acute transplant failure occurs within a few months of the transplantation procedure (a typical timeline is about three to twelve months after transplant). Almost no operation is completely without complications as antigens never completely match, so acute transplant failure is fairly common to some degree for every transplant recipient (“Transplant rejection,” MedlinePlus Medical Encyclopedia, n. d.). However, when monitored and treated early, this type of failure is reversible. Further, the chances of rejection decline as time goes on as the organ continues to function well in the body (“Understanding Transplant Rejection,” n. d.).

Chronic transplant failure occurs most gradually and refers to rejection any time after twelve months have passed. Even years after the transplantation has taken place, the individual’s immune system can continue to attack the transplanted organ and surrounding tissues in the body. This expends the body’s energy resources unnecessarily over a long period of time, puts strain on the immune system, and damages the transplanted organ (“Transplant rejection,” MedlinePlus Medical Encyclopedia, n. d.). Chronic failure is often difficult to detect because there are no early symptoms. There is currently no medication available to treat chronic failure, but, in some cases, the organ may be able to be removed, and the individual might have the opportunity to receive another transplant in the future (“Understanding Transplant Rejection,” n. d.). Unfortunately, there remain no true solutions to chronic transplant rejection, making it the most problematic form of rejection researchers are currently contending with.

The Natural Immune System

A general understanding of the body’s natural immune system is critical to understanding transplant immunology. The immune system refers to the complex system of cells, proteins, and organs that function to protect the human body from foreign antigens. Researchers have split immune organs and tissues into two main classes. The first is primary lymphoid organs (PLOs), which include the bone marrow and the thymus (Institute for Quality and Efficiency in Health Care, 2020). Bone marrow creates B-cells, while the thymus produces mature T-cells (“What are the organs of the immune system?”, 2006). The second is secondary lymphoid organs (SLOs), which include the spleen, tonsils, various mucous membranes, and the lymph nodes (LNs) (Institute for Quality and Efficiency in Health Care, 2020). It is in these SLOs that the immune system actively traps foreign antigens and activates the immune system. The spleen specifically stores various immune system cells, aids in filtering the blood stream, and breaks down red blood cells and platelets (“What are the organs of the immune system?”, 2006).

There are two forms of immunity provided by the immune system: innate and adaptive. Innate immunity, the first line of defense against antigens, consists of anatomic, physiologic, phagocytic, and inflammatory barriers. Anatomic barriers include epithelial cells found in the skin and lining the gastrointestinal tract and lungs. These anatomic barriers have pattern recognition receptors that allow them to instruct epithelial stem cell responses, alert neighboring cells, recruit immune cells, and repair damage (Larsen, et. al. 2019). On the other hand, physiological barriers, which are barriers that are a result of the body’s natural biology, include enzymes in saliva that break down antigens, the acidic environment of the stomach, the fever response, the release of interferons, and the functions of lysosomes (Marshall, et. al., 2018). Phagocytic cells can recognize both antigens and apoptotic cells (cells programmed for apoptosis, or cell death) and destroy them, making them useful for both fighting infection and tissue regulation (Rosales, Uribe-Querol, 2017). Within the phagocytic classification of the innate immune system, there are multiple cell types that carry out cytotoxic tasks and several cell types that play regulatory roles. Finally, the inflammatory response is triggered by the rapid production of molecules called cytokines, which are proteins critical to immune cell signaling, and chemokines, which signal activation of the fever response and cell recruitment to the affected area (Marshall, et. al., 2018). The response is characterized by redness, swelling, heat, and pain. With the exception of chronic inflammation, inflammation is naturally resolved with the resolution of injury or infection (Chen, et. al., 2017).

The adaptive immune system consists of the T-cells and B-cells produced by the thymus and bone marrow respectively. Each of these cells shows the ability to discern the body’s own cells from foreign cells and retain an immunological memory of these distinctions. T-cells, so named because they mature in the thymus, have a wide range of T-cell receptors (TCRs) that rely on antigen presenting cells to recognize and bind to specific foreign peptides. Once bound, TCRs signal for the T-cell to differentiate into helper T-cells or cytotoxic (killer) T-cells. Cytotoxic T-cells aid in the destruction of infected cells, and helper T-cells help mediate the immune response through the production and release of several different types of cytokines. After the infection has been resolved, most of these cells are cleared by phagocytes except for a few memory T-cells that remain in case of a recurring infection. B-cells, so named because they mature in the bone marrow, have antigen specific binding receptors. When antigens bind to the B-cells’ receptors, B-cells are activated and differentiate into effector cells or memory B-cells. When the body is battling infection, effector B-cells release antibodies; after, they undergo apoptosis, cell-mediated death, and are cleared. Memory B-cells are long-term, and they retain their antigen-binding receptors in order to quickly reactivate upon reinfection (Marshall, et. al., 2018).

Figure 2: This image shows the process of differentiation of T and B-cells. It is triggered by a T-cell identifying antigens on an antigen presenting cell (APC), and then activating the immune response to clear the infection.

Image Source: Wikimedia Commons 

Historical Advancements in Transplant

The origins of transplantation date back to as early as the second century. However, a lack of historical documentation means that researchers today have a lack of clarity surrounding the specific procedures and rejection rates of the transplanted regions going back before the sixteenth century (SciShow, 2018). Records improved in the late sixteenth century with Italian surgeon Gaspare Tagliacozzi’s illustrated book “On the Surgery of Mutilation by Grafting.” In this book, Tagliacozzi explores surgical techniques for skin graft procedures and the science behind skin graft rejection. One crucial insight Tagliacozzi offers is that homografts, tissue from the patient’s own body, were generally rejected less than allografts, or tissue from other people’s bodies (Tagliacozzi, 1597). He attributed this to “the force and power of individuality,” which we now understand to be manifested as the specificity of the individual immune system.

Figure 3: An image from Gaspare Tagliacozzi’s illustrated book De curtorum chirurgia that shows a man recovering after a nose transplantation. 

Image Source: Wikimedia Commons

After Tagliacozzi, early transplantation saw two major landmark technical advances. The first was the prioritization of antiseptic surgery, which was popularized by the British surgeon Joseph Lister in the late 19th century. Early antiseptic surgery involved handwashing and sterilizing wound dressings, instruments, and operating rooms with the microbe-killing chemical carbolic acid, first used by Lister in 1865. These techniques let surgeons operate with a smaller risk of infection and lower mortality rates for the patient (Lister, 1867). Moreover, the decrease in infection resulted in a decrease in the rejection of the transplanted grafts as there was significantly less chance of graft contamination before or during the procedure. 

The other major technical advancement came in 1869, when Jacques-Louis Reverdin discovered that small, thin (split thickness) grafts would heal as opposed to full thickness grafts that were met with a higher rate of rejection (Reverdin 1869). He was able to use autogenous “pinch grafts” to successfully cover burns, ulcers, or open wounds, with other surgeons soon replicating his efforts (Barker and Markmann, 2013). 

The origins of modern transplant immunology lie in 1890 with German physiologist Emil von Behring and Japanese bacteriologist Kitasato Shibasaburō, who theorized that microorganisms  assault the body while the body defends itself through a humorous mechanism; humoral immunity (and its associated mechanisms and pathways) refer to the type of immunity mediated by antibodies, proteins, peptides, and other macromolecules found in bodily fluids, or humors (Lindenmann, 1984). Another critical finding was made in 1902 by Danish biologist Carl Jensen, who was the first to characterize the failure of tumor homografts as having immunological root. However, Jensen’s explanation was largely discounted by the scientific community because no antibody could be detected. At the time, presence of antibodies was critical in determining whether an immune response was occurring (Barker and Marmann, 2013). Despite this setback, the role of immunity in skin graft rejection remained the central focus for new research.

By the end of the 1920s, American virologist James B. Murphy at the Rockefeller Institute established the role of the lymphocyte. Murphy found that if adult chicken spleen cells–the cells that mostly contain lymphocytes–were added to chicken embryos, then these embryos could be granted immunity against tumor implants (Hamilton, 112, 2012). Thus, Murphy concluded that tumor graft rejection was dependent on the lymphoid system. Subsequently, Murphy sought to extend graft survival by eliminating foreign lymphocytes with irradiation, splenectomy, or Benzol (a kind of chemical immunosuppressant) (Murphy and Ellis, 1914). Confined by the paradigm that lymphocytes were nonmotile and therefore did not travel around the body, Murphy could not explain his the reason behind the extended graft survival.

Also during this time, German physician Georg Schöne, widely accepted as the first transplant immunologist, discovered the “second set response” in 1912. Through skin homografts on mice, Schöne confirmed that when grafted twice, homograft tissue transplants failed faster the second time than the first (Hamilton, 112, 2012). Attributing this faster rate of tissue loss to a humoral pathway, Murphy and Schöne’s work remained pivotal in setting the foundation for twentieth century transplant immunology. Much of their work has been corroborated and built on by modern day researchers (Hamilton, 114, 2012).

Improvements in surgical kidney transplant procedures enabled further progress in the field. French Surgeon Alexis Carrel pioneered the system of vascular anastomosis, the suturing of two blood vessels, which is critical for the restructuring of blood flow (Carrel, 1902). Carrel’s methods remained vital during early experimental donor to recipient transplantations, with French surgeon Mathieu Jaboulay using Carrel’s technique to attempt the first human kidney transplantation two years later. Using a pig and goat kidney, transplanted into human patients, Jaboulay found that both kidneys functioned immediately after the procedure. This landmark surgery would remain the only successful human kidney transplant in the next few decades. However, following years of failed experimentation, the field of transplantation shifted from xenografts to human autografts and their immunological barriers. Xenografts refer to tissues from a donor of a different species than the recipient, while autografts are from donors that are the same species as the recipient.

While most research agencies halted their work during both World Wars, burn-related injuries – significant in this time period because of the number and severity of burns soldiers incurred in battle– kept transplant research in focus (Hamilton, 174, 2012). In 1943, Scottish surgeon Tom Gibson and British biologist Peter Medwar, unaware of Schöne’s previous findings on the second set response, confirmed the effect and renamed it the “second set mechanism”, observing it in action against skin homografts (Gibson and Medwar, 1943). Six years later, Medwar and his postdoctoral fellow Rupert Billingham started testing whether skin grafts exchanged between either fraternal or identical cattle twins would be accepted. They found that while the identical twins accepted each other’s grafts as predicted, graft exchanges between mature, nonidentical twin cattle were also accepted, even if the cattle were of different sexes; acceptance of grafts from different sexes are particularly groundbreaking as it confirmed that the differences between male and female were not significant enough to prevent inter-sex transplantation (Andreson et al., 1951).

Australian biologist Frank Burnet advanced this hypothesis, finding that in utero, cells gradually acquire the ability to differentiate between self and non-self cells (Burnet, 1949). With Billingham, Dr. Peter Medwar, a British biologist, published a seminal paper in 1951 on grafting techniques and found that inducting chimerism into grafts would allow for acceptance of foreign tissue. Chimerism refers to cells with multiple distinct genotypes. “Mixed chimerism” occurs when recipient lymphohematopoietic systems contain both host and donor cells (Sachs et al., 2014) Outside of successfully altering the immunity mechanism to accept allografts, they demonstrated that the lymphocyte was a motile cell, directly responsible for graft rejection (Barker and Marmann, 2013). 

Medwar and Buret’s paradigm shift directly laid the foundation for the first successful kidney transplant in humans. In 1954, American surgeon Joseph Murray performed the world’s first successful renal transplant between identical twins. But because induction of chimerism in human recipients by neonatal treatment was clearly impossible, another approach would be necessary. The following year, American pathologist Richmod Prehn and his laboratory assistant, Joan Main, demonstrated that weakening the immune system of adult mice by radiation allowed them to induce chimerism by inoculating bone marrow cells, which allowed for expression of multiple genotypes (Main and Prehn, 1955). In 1959, Murray used the Main-Prehn technique between two human kidney recipients, which involved conditioning the graft with total body irradiation and bone marrow. Although eleven of the twelve irradiated patients died within the first month, the twelfth patient was able to survive with his fraternal twin brother’s kidney for twenty years (Barker and Marmann, 2013). 

While the rest of the decade remained focused on refining surgical methods and expanding which organs were transplanted, the next leap in the field was centered around improvements in immunosuppressive drugs. At the 1963 National Research Council Conference, American physician Thomas Starzl presented his treatment with prednisone-azanthopine, an immunosppressent, which led to a greater than 70% 1-year renal graft survival rate (Hamilton, 279-280, 2012). Starzl’s Cyclosporin A would remain the world standard for immunosuppressants for almost the next two decades until the use of cyclosporine, a fungal derivative presented by Jean-François Borel in 1976, and tacrolimus, derived by Starlz in 1989 (Allison, 2000). Starzl remains known as the “father of modern transplantation” for not only establishing the clinical utility of cyclosporine, but also performing the first successful liver transplant in 1963 (Eghtesad and Fung, 2017). While the evolution of organ transplantation remains one of modern medicine’s most inspiring narratives, future breakthroughs in immunology mean that the promise of complete organ graft acceptance to be imminent.

Key Immunological Concepts

Arguably, the most critical advances in immunology came from understanding of the Major Histocompatibility Complex (MHC) and Human Leukocyte Antigens (HLAs). MHC molecules controls how the immune system detects and responds to specific antigens. In humans, these molecules are called HLAs and are located on chromosome 6. There are two classes of HLA molecules: Class I and Class II. Class I molecules are composed of a polymorphic (containing multiple gene variants) heavy chain (α chain, 44 kDa) and a non-polymorphic light chain (β2 microglobulin, 12 kDa). They are expressed on all nucleated cells and generally present small antigens (typically 9 to 11 amino acids). Class II molecules (HLA-DP, -DQ, and -DR) are composed of a polymorphic α chain (35 kDa) and a β chain (31 kDa) (Janeway et. al., 2001). They are constitutively expressed only on professional antigen-presenting cells (APC), including dendritic cells, macrophages, and B-cells (Nesmiyanov, n.d.). 

The degree of HLA mismatch between donor and recipient plays a significant role in determining the risk of chronic rejection and graft loss. The MHC is involved in the direct mechanism of allorecognition, where T-cells recognize determinants on the donor MHC molecule-peptide complex displayed at the cell surface. In essence, this means that MHCs play a critical role in recognition of non-self as T-cells recognize molecules on the donor MHCs (Neefjes et al, 2011) The MHC molecules display an antigenic determinant that recognizes antigens from the transplanted cells as non-self (Fernando et al, 2008). Risk of organ transplantation comes from the alloresponse, where the histo-incompatible antigen (antigens that are foreign to the recipient) is recognized, producing a response from the adaptive immune system via the employment of allospecific T-cells. T-cell antigen recognition is is controlled by MHC molecules; different antigen presentation between MHC class I and class II molecules can lead to rejection of the transplanted tissue (Janeway et al, 2001). To prevent an alloresponse in non-tolerant recipients, immunosuppressive drugs are provided.

Indeed, HLAs are crucial to preventing rejection. However, even in cases where the tests reveal that HLAs between the donor and recipient are identical, acute and chronic rejection still occurs (Kumbala & Zhang, 2013; Zhang & Reed, 2017). This rejection indicates that there is an immune response to non-HLA antigens. Despite playing a smaller role in graft-versus-host disease (GVHD), a disease in which the donor cells from the transplant attack the recipient’s body (discussed in detail later in this paper), non-HLA antigens are important in characterizing what cells are self and non-self. For example, blood type matching is critical when determining the risk of GVHD in transplantation. Blood contains glycoprotein hemagglutinin, which comes in types A and/or B. This protein is expressed on vascular endothelial cells and if matched incorrectly (for example, if a Type A person gets Type B blood), the immune system may recognize them as non-self. This, in turn, causes GVHD. On the other hand, the rhesus factor (positive if Rh immunoglobin is present on the red blood cells and negative otherwise) is not relevant to transplantation as it is not expressed on the endothelium of blood vessels (meaning that a Type A+ person can get a transplant from a Type A- person), illustrating that non-HLAs have varying impacts on rejection (Kumbala & Zhang, 2013). 

The minor histocompatibility antigens (MiHA) are an extremely diverse group of non-HLAs. They primarily interact with CD8 cytotoxic T-cells and B-cells through the MHC. One of the most well-known examples of MiHAs is the H-Y MiHA, which the Y chromosome of males encodes. When this is detected in a female, this elicits a non-self identification response (Kumbala & Zhang, 2013). More research is required on MiHAs as their impact on GVHD is largely understudied. Most utilize proteomics, the study of proteins, to correctly assess this. There are many differences that can occur post translation, so mere genomics provides incomplete insight into the differences between the donor and recipient MiHAs (Roy & Perreault, 2017). Thus, using single nucleotide polymorphisms as a surrogate for mismatching MiHAs could possibly underrepresent the disparity.

Understanding the behavior of T cells and their co-stimulatory pathways is also critical to understanding transplantation. The primary signal for T-cell activation occurs through T cell receptor stimulation by an antigen presented on the MHC of an APC. This pathway can be broken down into three subsets: semidirect , direct, indirect. Regarding transplantation, the semi direct pathway, which involves APCs presenting intact donor HLAs, has little importance. In the direct pathway, donor cells directly present their HLAs to the recipient T-cells, causing GVHD. This is critical during the immediate transplant period. In the early stages of the transplant, the recipient T-cells would immediately recognize the graft as non-self without sufficient immunosuppression. In the indirect pathway, recipient APCs present fragments of the donor HLA to T-cells. It is significantly less important in the immediate transplant period than the direct pathway. It more importantly plays a role in late onset rejection and chronic rejection. Because recipient APCs can continue to present donor HLAs throughout the lifetime of the allograft, consistent immunosuppression is required to prevent rejection (Kumbala & Zhang, 2013).

In order to activate a T-cell, the APC must possess a costimulatory ligand in addition to the antigen presented on its MHC. Without co-stimulation, the T-cell enters a state of dormancy, and no response is mounted to the antigen. For this reason, targeting and inhibiting co-stimulation may serve as a viable option to regulate rejection. The principal costimulatory receptor/ligand pair is CD28/B7. The ligation of CD28 on T-cells by B7 on APCs causes T-cell activation, increasing proliferation and countering apoptosis. Cytotoxic T lymphocyte associated antigen 4 (CTLA4), which also binds to B7 with greater affinity, begins being expressed following T-cell activation. When B7 activates CTLA4, the T-cell response is dampened. For this reason, CTLA4 has been explored as a possible immunosuppressive treatment (Martinez & Rosen, 2005).

The CD40/CD154 costimulatory pathway is critical in alloimmune responses. While CD154 is predominantly expressed on CD4 T-cells (CD8, NK, B-cells to a lesser extent), CD40 is expressed on APCs, including macrophages and dendritic cells. In contrast to CD28/B7, CD40/CD154 ligation results in enhancements to the APC, upregulating class II MHC, CD80, and CD86 expressions and producing cytokines. This augments T and B-cell responses to the alloantigen (Martinez & Rosen, 2005). Anti-CD154 is used to inhibit this costimulatory pair. In murine studies, it is as effective as CTLA4; however, it injures biliary and endothelial cells less than CTLA4 (Bartlett et. al, 2002).

While CD28/B7 and CD40/CD154 play significant roles in rejection, other pathways are being explored. Following T-cell activation, inducible co-stimulator (ICOS) is expressed on the T-cells on the APC. This pathway induces proliferation, cytokine production, and B-cell activation. It can also possibly induce T regulatory cell development and interferon-𝛾 (IFN𝛾) production, which is a cytotoxic molecule (Martinez & Rosen, 2005).

When the T-cell is presented with an antigen and co-stimulation, the T-cell activates. It does so through three pathways: the calcium-calcineurin pathway (which effects the cell membrane), the RAS-mitogen activated protein (MAP) kinase pathway (which effects surface-to-nucleus signaling), and the IKK-nuclear factor κB (NF-κB) pathway (which effects cytokine production and cell survival) (Martinez & Rosen, 2005).

Following activation, the T-cell begins to secrete various cytokines, including interleukin-2 (IL-2). IL-2 enables T-cell proliferation, which causes the T-cell to become either a CD4 or CD8 T-cell. CD8 cytotoxic T-cells proceed to eliminate the non-self cells, inducing apoptosis. CD4 helper T-cells proceed to assist macrophages and B-cells, increasing antigen presentation. A small subset of activated T-cells will become memory T-cells, which remember the antigen that activated the T-cells.

Current Key Areas of Study

As the field of transplant immunology continues to evolve, researchers are progressing in several separate areas that could lead to breakthroughs in transplant procedures. The last section of this paper discusses four of these specialized areas: tertiary lymphoid structures, graft-versus-host disease, stem cell transplant, and immune tolerance and immunosuppressants. 

The Role of Tertiary Lymphoid Structures (TLS) in Transplant Rejection 

As previously discussed, researchers have developed a good understanding of the anatomy of the human immune system. They have split the organs and tissues that immune cells reside in into two categories: PLOs, which include the thymus and bone marrow, SLOs, which include the spleen, tonsils, various mucous membranes, and lymph nodes (Institute for Quality and Efficiency in Health Care, 2020). These organs and tissues are highly organized and, for the most part, their role in the immune system and immunological applications are well understood. However, in the early 1990s, researchers began to categorize ectopic lymphoid structures that were found in non-lymphoid tissues and organs (see Figure 3). They were deemed tertiary lymphoid structures (TLS) (Pipi et. al., 2018). 

Figure 4: Lymph nodes are found in several parts of the body, as depicted in this image. TLS have been found in several other areas, including the kidneys, heart, pancreas, synovium glands, and salivary glands (Pipi et. al., 2018).

Image Source: Wikimedia Commons

TLS are formed in chronically inflamed tissue in a process called lymphoid neogenesis. Their structures share many similarities to LNs. Both have distinct and separate zones for B and T-cells (Colbeck et. al., 2017). There are also stark similarities between these zones. In T-cell zones, both TLS and LS contain developed fibroblastic reticular cellular networks, which contain collagen and act as conduits for molecular distribution throughout the structure (Colbeck et. al., 2017; Textor et. al., 2016). Additionally, both have high endothelial venules (HEVs), which are sites of antigen presentation and recognition and also provide connections between the structures and rest of the body (Colbeck et. al., 2017; Ruddle, 2016). In B-cell zones, both TLS and LS contain follicular dendritic cells, which have a critical role in B-cell activation and maturation (Colbeck et. al., 2017; Kranich & Krautler, 2016). Researchers have found evidence of B-cell classes switching in TLS, an important process B-cells in LNs undergo when activating. There are key differences between TLS and LS; notably, TLS are not encapsulated like LNs, indicating that TLS are significantly less developed and organized than LS. This is because TLS are formed postnatally in inflammatory conditions, while LNs are formed prenatally and are genetically preplanned (Colbeck et. al., 2017).

TLS have been noted in allografts, as chronic rejection provides the setting of chronic inflammation where TLS forms. Subsequently, transplant immunologists have been studying the role of TLS in allograft acceptance and rejection for the past few decades. The current generally accepted hypothesis is that TLS contribute to chronic rejection by supporting local alloimmune response against allografts. However, researchers have also noted TLS in both accepted allografts, which could mean that TLS control rather than propagate the body’s alloimmune response (Koenig & Thaunat, 2016). Currently, there is significantly more evidence for the former. Critically, researchers have demonstrated that TLS can activate naive T-cells, which researchers believe would contribute to rejection by strengthening local immune attack against the transplanted organ (Nasr et. al., 2007). Additionally, researchers have found evidence of naive B-cell activation and similarities between TLS and LN T-cell-dendritic cell interaction. Naive B-cell activation, similar to naive T-cell activation, would hypothetically strengthen local immune attack against a graft. TLS-LS similarity further supports TLS propagating local alloimmune response, as LN activation of immune cells is at the core of not just alloimmune response but of all immune responses in the body (Abou-Daya et. al., 2019). 

Graft-Versus-Host disease 

Although medical professionals take great precautions in order to prevent postoperative complications after allogeneic transplantation surgery, it is not risk-free. There are two complications. The first is a host-versus-graft reaction, in which the recipient’s immune system attacks the graft; this can lead to graft rejection, thus invalidating the transplant process and putting the patient at risk. Perhaps more dangerous is a graft-versus-host reaction, which can lead to graft-versus-host disease (GVHD). These occur after the transplantation of blood products, bone marrow, and organs; critically, all of these transplants involve transfer of T-cells (Ferrara et. al., 2009). The donor cells identify the recipient’s cells as foreign. This triggers an immune response in which the donor T-cells attack the recipient’s tissue. The severity of the complication varies greatly from one patient to another, but there is still no consistent way to prevent GVHD. Typically, medical professionals will both remove T-cells from the graft and medicate the donor tissue with immunosuppressants like Methotrexate and Cyclosporine (Leukemia and Lymphoma Society, 2015). While this method may lessen the severity of the complication, GVHD is still the most frequent complication of cell transplantation (Moreno & Cid, 2019). 

GVHD is broken down into two types – chronic GVHD (cGVHD) and acute GVHD (aGVHD). Both share similar symptoms but have different timelines; aGVHD is diagnosed before the 100-day mark, and it is the main fatal complication of organ transplant (Moreno & Cid, 2019). Studies have shown that aGVHD can lead to complications in the skin, gastrointestinal tract, and liver (Martin et. al., 1990). The most common skin complication is a maculopapular rash, which is characterized by the presence of red spots and raised skin lesions (Leonard, 2018). Gastrointestinal symptoms caused by aGVHD involve diarrhea and bleeding, and liver symptoms can include the inflammation of bile ducts. (Ferrara, et. al., 2009).

In contrast, cGVHD remains as one of the most common long-term postoperative complications. cGVHD is diagnosed 100 days after transplantation, and its presence decreases the likelihood of a successful transplant due to risks of both death and disability in organ recipients. Signs of cGVHD typically begin in the the buccal mucosa (see Figure 4). Additionally, symptoms can be present in the skin, liver, kidneys, heart, GI tract, and mouth. There are two main risk factors for cGVHD. The first is age – elderly patients are more susceptible to immune complications because their natural immune systems are weaker than their younger counterparts. The second is having had aGVHD in the past, as this can also significantly weaken the immune system. Strategies that are used to prevent aGVHD may also prevent cVHD as well (Ferrara et. al., 2009). 

Figure 5: Pictured is the anatomy of the mouth. The buccal mucosa refers to the inner lining of the cheeks and backs of the lips.

Image Source: (Wikimedia Commons)

Unfortunately, the pathophysiology of cGVHD remains poorly understood, and this is likely why the response of cGVHD to treatment is largely unpredictable (Ferrara et. al., 2009). Typical treatment involves long-term immunosuppression, which can be particularly dangerous as it makes patients increasingly susceptible to pathogens (Sergeyenko et. al., 2018).

For both aGVHD and cGVHD, the severity is directly related to the dissimilarity between human leukocyte antigen proteins in the donor and recipient tissue (Ferrara, et. al., 2009). The greater the dissimilarity, the greater the severity of GVHD. Both cGVHD and aGVHD are problematic issues that need to be addressed. For those who do not have an identical twin, there is a risk of GVHD after a transplant operation. Without a consistent way to prevent GVHD, medical professionals could be saving one’s life with the transplant procedure while introducing a new, bigger problem into patients’ lives. 

Stem Cell Transplant 

There are three different types of stem cells in the human body throughout its life cycle. The first, embryonic stem cells, are only present in embryos and can give rise to all cell types. The other two are types of adult stem cells (ASCs). Pluripotent stem cells (PSC) can give rise to any cell type except embryonic cells; multipotent stem cells (MSC) also give rise to multiple cell types, but the differentiation options are limited (i.e. there are some cells MSCs cannot differentiate into). Some well-known stem cell types include like hematopoietic, epithelial, muscular, and neural; however, stem cells can be found throughout the body. It can be hard to discern them from differentiated organ tissue, as some lack markers that generally distinguish stem cells. The most common source of ASCs is the bone marrow (Chagastelles, Nardi, 2011).

The most common use of stem cell transplantation is multipotent hematopoietic stem cell transplantation through bone marrow and blood transplants. This process can use the patient’s own stem cells, cells of a donor, or cells of an identical twin. The results of transplants from allogeneic transplants are improving, likely due to improved safety of these grafts through reduced conditioning training of patients, lymphocyte infusions, higher quality of human leukocyte antigen (HLA) matching, and improved care of patients. It has also been shown that the use of umbilical cord or peripheral blood stem cell donation are associated with lower risk of host-versus-graft disease (not to be confused with graft-versus-host disease) (Lennard, Jackson, 2000). The immune system can recognize undifferentiated stem cells, which limits their survival and potential beneficial effects; developing a strong understanding of stem cell immunogenicity is vital to the continued development of stem cell transplantation (Miller, Schrepfer, 2017). 

Following allogeneic stem cell transplantation, the host’s immune system takes time to recover and often never fully does due to the impacts of immunosuppressants and the extremely invasive nature of transplant procedures. Innate immunity recovers rather quickly after transplantation; in fact, just one month after transplant, natural killer (NK) cells have shown to be circulating regularly and providing some function of immunity. However, it can take 1-2 years for B-cells to reach normal adult levels, and the process of turning thymocytes into mature T-cells is decreased or even eliminated following transplantation. To remedy this, there are a few alternate pathways including increased donation of mature T-cells and rapid division of mature T-cell clones, although this is not a stable process showing declining numbers of T-cells after 3-6 months. To avoid these risks, the now most common type of stem cell transplantation is autologous transplantation. Currently, bone marrow can be safely preserved through cryopreservation. In both these methods, the donor and the host are the same, so there is limited risk of host-versus-graft disease or immunosuppression (Williams, Gress, 2008).

Alongside immunological concerns, there is a bioethical debate concerning communication in the consent of stem cell transplantation and the social and ethical concerns of offering such expensive procedures (Liso, et. al., 2017). A turning point in stem cell transplantation occurred in 2006 when scientists Shinya Yamanaka and Kazutoshi Takahashi found that PSCs can be induced from MSCs; these new cells are referred to as induced pluripotent stem cells (iPSCs). This method avoids the issue of a negative immunological response, as the transplanted stem cells come from the host themselves (Zakrzewski, et. al., 2019). However, it comes with its own set of issues as well. Similar to allogeneic transplants, there are bioethical concerns in production cost and the time it takes to produce the necessary amount of clinical quality cells. There is also concern that transplanted cells have higher genetic instability and less maturity than their natural counterparts, or that they retain epigenetic memory from their somatic cell sources. Also, some studies have shown rejection of syngeneic (genetically identical) cells, while others have shown no issue (Doss, Sachinidis, 2019). Finally, even though theoretically, manipulation of cells in vivo would allow for most easy transition into the body’s preexisting tissue, there are several challenges due to the many factors that cannot be controlled (Zakrzewski, et. al., 2019).

Current State of Immune Tolerance and Immunosuppressants in Transplantation

For a successful transplant to occur, the recipient and the donor organ must develop a degree of immune tolerance against the antigens that each present, thus preventing both a host-versus-graft reaction and GVHD. By producing immune tolerance in a patient, the risk of graft failure or further post-transplantation complications in both types of reactions decreases. The goal of immune suppression prior to transplantation is twofold: 1) reduction of T-cell maturation and 2) suppression of self-reactive T-cells. It has been shown that the induction of transplant tolerance has improved transplantation outcomes (Alpdogan and Van den Brink, 2012).

While the current system of immunosuppression to reduce postoperative complications of transplantation surgery has been shown to improve patient outcomes, it is undeniable that there are dangerous, unwanted side-effects. The most obvious and dangerous side effect is the increased risk of infection and weakened immune system. Although they continue to be the state-of-the-art treatment for transplant patients, existing immunosuppressants put a patient at great risk of contracting an infection and lessen their ability to fight it off (Niethammer et. al., n.d.). Further research must be conducted in order to find an alternative solution that can avoid organ rejection whilst still keeping the body’s immune system intact and operating optimally.

Pharmacological researchers work in combination with transplant immunologists to develop immunosuppressants for transplant patients. These collaborations keep the body’s immune response at bay and significantly lengthen the lifespan of transplanted organs and the people using them. The different types of immunosuppressant drugs can be broken down into three main categories: induction, maintenance, and rejection treatment drugs (Kalluri, 2012). Induction immunosuppressants are those used at the time of transplantation to prevent hyperacute and acute rejection of the allograft; typically, these are monoclonal or polyclonal antibodies and help to inhibit IL-2, a cytokine critical to the regulation of lymphocytes (Kirk, 2006). Doctors typically employ a combination of drugs; some more recent drugs include alefacept, alemtuzumab, and efalizumab (Kalluri, 2012). Each of these promote allograft acceptance and reduce the body’s natural immune response in different ways. Alefacept reduces the numbers of memory T-cells in the host body (Lee et. al., 2013). Alemtuzumab causes a general depletion of B and T-cells in the allograft recipient for several months after transplant (van der Zwan et. al., 2018). Efalizumab blocks naive B and T-cell activation (Efalizumab, 2012). These and other induction immunosuppression have been shown to significantly decrease acute rejection, though there are still questions about their role in long term allograft acceptance (Kirk, 2006).

Maintenance therapies contain four different drug classes. The first is calcineurin inhibitors, which inhibit the enzyme calcineurin, the enzyme that activates naive T-cells (Kalluri, 2012; Calcineurin inhibitors, n.d.). The second is mammalian target of rapamycin (mTOR) inhibitors, which inhibit mTOR, the protein kinase involved in stimulation of cell growth and angiogenesis (Kalluri, 2012; MTOR inhibitors, n.d.). The third is antiproliferative agents, which prevent multiplication of immune cells (Kalluri, 2012; University of Wisconsin, n. d.). The fourth is corticosteroids, which help to reduce inflammation (Kalluri, 2012; Cleveland Clinic, 2020). Recent maintenance agents include belatacept, sotrastaurin and tofacitinib (Kalluri, 2012). Belatacept is a selective T-cell co-stimulation blocker that blocks the interaction between CD80/86 ligands and CD28, an interaction that is critical to cytotoxic T-cell proliferation, the event that is arguably the biggest contributor to allograft rejection (Melvin et. al., 2012). Sotrastaurin is a protein kinase c-inhibitor that blocks T-cell activation by disrupting NF-κB signaling pathways, which lead to ischemia (reduced blood flow) and eventual transplant rejection (Evenou et. al., 2009). 

Once an organ enters acute rejection, the drug class used depends on the severity of rejection. There are two main types of acute rejection. The first is cellular. For more mild cellular rejection, doctors often opt to use corticosteroids to reduce inflammation (Kalluri, 2012). For more severe cellular rejection, doctors use antithymocyte globulins; though their mechanism of action is still being studied, these globulins may help deplete T-cells bortezomib and eculizumab (Mohty, 2007). The second type of acute rejection is humoral, which is much more difficult to treat than cellular rejection (see Figure 5). Doctors often opt to use immunoglobulins and plasmapheresis. Drugs currently being used for humoral rejection treatment include bortezomib and eculizumab (Kalluri, 2012). Bortezomib is a proteasome inhibitor that works to reduce anti-HLA antibodies (Lee et. al., 2015). Eculizumab cleaves the protein C5, which prevents the formation of the membrane attack complex, a critical effector protein of the immune system (Barnett et. al., 2013). Overall, current immunosuppressants are quite effective, as the rate of acute rejection has dropped to minimal levels in many transplant centers. Researchers will continue to look into methods to maximize the lifetime of allografts while limiting negative side-effects (Kalluri, 2012).

Unfortunately, the pathophysiology of cGVHD remains poorly understood, and this is likely why the response of cGVHD to treatment is largely unpredictable (Ferrara et. al., 2009). Typical treatment involves long-term immunosuppression, which can be particularly dangerous as it makes patients increasingly susceptible to pathogens (Sergeyenko et. al., 2018).

For both aGVHD and cGVHD, the severity is directly related to the dissimilarity between human leukocyte antigen proteins in the donor and recipient tissue (Ferrara, et. al., 2009). The greater the dissimilarity, the greater the severity of GVHD. Both cGVHD and aGVHD are problematic issues that need to be addressed. For those who do not have an identical twin, there is a risk of GVHD after a transplant operation. Without a consistent way to prevent GVHD, medical professionals could be saving one’s life with the transplant procedure while introducing a new, bigger problem into patients’ lives. 

Stem Cell Transplant 

There are three different types of stem cells in the human body throughout its life cycle. The first, embryonic stem cells, are only present in embryos and can give rise to all cell types. The other two are types of adult stem cells (ASCs). Pluripotent stem cells (PSC) can give rise to any cell type except embryonic cells; multipotent stem cells (MSC) also give rise to multiple cell types, but the differentiation options are limited (i.e. there are some cells MSCs cannot differentiate into). Some well-known stem cell types include like hematopoietic, epithelial, muscular, and neural; however, stem cells can be found throughout the body. It can be hard to discern them from differentiated organ tissue, as some lack markers that generally distinguish stem cells. The most common source of ASCs is the bone marrow (Chagastelles, Nardi, 2011).

The most common use of stem cell transplantation is multipotent hematopoietic stem cell transplantation through bone marrow and blood transplants. This process can use the patient’s own stem cells, cells of a donor, or cells of an identical twin. The results of transplants from allogeneic transplants are improving, likely due to improved safety of these grafts through reduced conditioning training of patients, lymphocyte infusions, higher quality of human leukocyte antigen (HLA) matching, and improved care of patients. It has also been shown that the use of umbilical cord or peripheral blood stem cell donation are associated with lower risk of host-versus-graft disease (not to be confused with graft-versus-host disease) (Lennard, Jackson, 2000). The immune system can recognize undifferentiated stem cells, which limits their survival and potential beneficial effects; developing a strong understanding of stem cell immunogenicity is vital to the continued development of stem cell transplantation (Miller, Schrepfer, 2017). 

Following allogeneic stem cell transplantation, the host’s immune system takes time to recover and often never fully does due to the impacts of immunosuppressants and the extremely invasive nature of transplant procedures. Innate immunity recovers rather quickly after transplantation; in fact, just one month after transplant, natural killer (NK) cells have shown to be circulating regularly and providing some function of immunity. However, it can take 1-2 years for B-cells to reach normal adult levels, and the process of turning thymocytes into mature T-cells is decreased or even eliminated following transplantation. To remedy this, there are a few alternate pathways including increased donation of mature T-cells and rapid division of mature T-cell clones, although this is not a stable process showing declining numbers of T-cells after 3-6 months. To avoid these risks, the now most common type of stem cell transplantation is autologous transplantation. Currently, bone marrow can be safely preserved through cryopreservation. In both these methods, the donor and the host are the same, so there is limited risk of host-versus-graft disease or immunosuppression (Williams, Gress, 2008).

Alongside immunological concerns, there is a bioethical debate concerning communication in the consent of stem cell transplantation and the social and ethical concerns of offering such expensive procedures (Liso, et. al., 2017). A turning point in stem cell transplantation occurred in 2006 when scientists Shinya Yamanaka and Kazutoshi Takahashi found that PSCs can be induced from MSCs; these new cells are referred to as induced pluripotent stem cells (iPSCs). This method avoids the issue of a negative immunological response, as the transplanted stem cells come from the host themselves (Zakrzewski, et. al., 2019). However, it comes with its own set of issues as well. Similar to allogeneic transplants, there are bioethical concerns in production cost and the time it takes to produce the necessary amount of clinical quality cells. There is also concern that transplanted cells have higher genetic instability and less maturity than their natural counterparts, or that they retain epigenetic memory from their somatic cell sources. Also, some studies have shown rejection of syngeneic (genetically identical) cells, while others have shown no issue (Doss, Sachinidis, 2019). Finally, even though theoretically, manipulation of cells in vivo would allow for most easy transition into the body’s preexisting tissue, there are several challenges due to the many factors that cannot be controlled (Zakrzewski, et. al., 2019).

Current State of Immune Tolerance and Immunosuppressants in Transplantation

For a successful transplant to occur, the recipient and the donor organ must develop a degree of immune tolerance against the antigens that each present, thus preventing both a host-versus-graft reaction and GVHD. By producing immune tolerance in a patient, the risk of graft failure or further post-transplantation complications in both types of reactions decreases. The goal of immune suppression prior to transplantation is twofold: 1) reduction of T-cell maturation and 2) suppression of self-reactive T-cells. It has been shown that the induction of transplant tolerance has improved transplantation outcomes (Alpdogan and Van den Brink, 2012).

While the current system of immunosuppression to reduce postoperative complications of transplantation surgery has been shown to improve patient outcomes, it is undeniable that there are dangerous, unwanted side-effects. The most obvious and dangerous side effect is the increased risk of infection and weakened immune system. Although they continue to be the state-of-the-art treatment for transplant patients, existing immunosuppressants put a patient at great risk of contracting an infection and lessen their ability to fight it off (Niethammer et. al., n.d.). Further research must be conducted in order to find an alternative solution that can avoid organ rejection whilst still keeping the body’s immune system intact and operating optimally.

Pharmacological researchers work in combination with transplant immunologists to develop immunosuppressants for transplant patients. These collaborations keep the body’s immune response at bay and significantly lengthen the lifespan of transplanted organs and the people using them. The different types of immunosuppressant drugs can be broken down into three main categories: induction, maintenance, and rejection treatment drugs (Kalluri, 2012). Induction immunosuppressants are those used at the time of transplantation to prevent hyperacute and acute rejection of the allograft; typically, these are monoclonal or polyclonal antibodies and help to inhibit IL-2, a cytokine critical to the regulation of lymphocytes (Kirk, 2006). Doctors typically employ a combination of drugs; some more recent drugs include alefacept, alemtuzumab, and efalizumab (Kalluri, 2012). Each of these promote allograft acceptance and reduce the body’s natural immune response in different ways. Alefacept reduces the numbers of memory T-cells in the host body (Lee et. al., 2013). Alemtuzumab causes a general depletion of B and T-cells in the allograft recipient for several months after transplant (van der Zwan et. al., 2018). Efalizumab blocks naive B and T-cell activation (Efalizumab, 2012). These and other induction immunosuppression have been shown to significantly decrease acute rejection, though there are still questions about their role in long term allograft acceptance (Kirk, 2006).

Maintenance therapies contain four different drug classes. The first is calcineurin inhibitors, which inhibit the enzyme calcineurin, the enzyme that activates naive T-cells (Kalluri, 2012; Calcineurin inhibitors, n.d.). The second is mammalian target of rapamycin (mTOR) inhibitors, which inhibit mTOR, the protein kinase involved in stimulation of cell growth and angiogenesis (Kalluri, 2012; MTOR inhibitors, n.d.). The third is antiproliferative agents, which prevent multiplication of immune cells (Kalluri, 2012; University of Wisconsin, n. d.). The fourth is corticosteroids, which help to reduce inflammation (Kalluri, 2012; Cleveland Clinic, 2020). Recent maintenance agents include belatacept, sotrastaurin and tofacitinib (Kalluri, 2012). Belatacept is a selective T-cell co-stimulation blocker that blocks the interaction between CD80/86 ligands and CD28, an interaction that is critical to cytotoxic T-cell proliferation, the event that is arguably the biggest contributor to allograft rejection (Melvin et. al., 2012). Sotrastaurin is a protein kinase c-inhibitor that blocks T-cell activation by disrupting NF-κB signaling pathways, which lead to ischemia (reduced blood flow) and eventual transplant rejection (Evenou et. al., 2009). 

Once an organ enters acute rejection, the drug class used depends on the severity of rejection. There are two main types of acute rejection. The first is cellular. For more mild cellular rejection, doctors often opt to use corticosteroids to reduce inflammation (Kalluri, 2012). For more severe cellular rejection, doctors use antithymocyte globulins; though their mechanism of action is still being studied, these globulins may help deplete T-cells bortezomib and eculizumab (Mohty, 2007). The second type of acute rejection is humoral, which is much more difficult to treat than cellular rejection (see Figure 5). Doctors often opt to use immunoglobulins and plasmapheresis. Drugs currently being used for humoral rejection treatment include bortezomib and eculizumab (Kalluri, 2012). Bortezomib is a proteasome inhibitor that works to reduce anti-HLA antibodies (Lee et. al., 2015). Eculizumab cleaves the protein C5, which prevents the formation of the membrane attack complex, a critical effector protein of the immune system (Barnett et. al., 2013). Overall, current immunosuppressants are quite effective, as the rate of acute rejection has dropped to minimal levels in many transplant centers. Researchers will continue to look into methods to maximize the lifetime of allografts while limiting negative side-effects (Kalluri, 2012).

Figure 6: Renal acute humoral rejection can be categorized by positive CD4 staining of the peritubular capillaries, as shown in this image. Peritubular capillaries work alongside nephrons (functional units of the kidneys) to reabsorb and secrete blood in the nephrons’ inner lumens (Rubenstein et. al., 2015).

Image Source: Wikimedia Commons

Conclusions 

Though there is much that researchers have discovered about the interactions between the immune system and transplanted organs, there are several areas that still need to be explored in order for researchers to find a long-term solution to chronic transplant rejection. As researchers continue to work in the field of transplant immunology, efforts will be made to both develop better immunosuppressants and advance understanding of mechanisms of rejection. Additionally, researchers may make a move towards smaller-scale, cell-based regenerative medicine using stem cells rather than allografts. The hope is that as more research is done, researchers will be able to develop methods to reduce transplant-related complications and increase the longevity of transplanted organs, giving transplant patients a better quality of life. 

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