Transplant rejection

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Transplant rejection
Lung transplant rejection - high mag.jpg
Micrograph showing lung transplant rejection. Lung biopsy. H&E stain.
Specialty Immunology
Treatment Immunosuppressive drugs

Transplant rejection occurs when transplanted tissue is rejected by the recipient's immune system, which destroys the transplanted tissue. Transplant rejection can be lessened by determining the molecular similitude between donor and recipient and by use of immunosuppressant drugs after transplant. [1]

Contents

Types of transplant rejection

Transplant rejection can be classified into three types: hyperacute, acute, and chronic. [2] These types are differentiated by how quickly the recipient's immune system is activated and the specific aspect or aspects of immunity involved. [3]

Hyperacute rejection

Hyperacute rejection is a form of rejection that manifests itself in the minutes to hours following transplantation. [4] It is caused by the presence of pre-existing antibodies in the recipient that recognize antigens in the donor organ. [5] These antigens are located on the endothelial lining of blood vessels within the transplanted organ and, once antibodies bind, will lead to the rapid activation of the complement system. [6] Irreversible damage via thrombosis and subsequent graft necrosis is to be expected. [7] Tissue left implanted will fail to work and could lead to high fever and malaise as the immune system acts against foreign tissue. [8]

Graft failure secondary to hyperacute rejection has significantly decreased in incidence as a result of improved pre-transplant screening for antibodies to donor tissues. [4] While these preformed antibodies may result from prior transplants, prior blood transfusions, or pregnancy, hyperacute rejection is most commonly from antibodies to ABO blood group antigens. [6] Consequently, transplants between individuals with differing ABO blood types is generally avoided though may be pursued in very young children (generally under 12 months, but often as old as 24 months) [9] who do not have fully developed immune systems. [10] Shortages of organs and the morbidity and mortality associated with being on transplant waitlists has also increased interest in ABO-incompatible transplantation in older children and adults. [11]

Acute rejection

Acute rejection is a category of rejection that occurs on the timescale of weeks to months, with most episodes occurring within the first 3 months to 1 year after transplantation. [6] [8] Unlike hyperacute rejection, acute rejection is thought to arise from two distinct immunological mechanisms as lymphocytes, a subset of white blood cells, begin to recognize antigens on transplanted organ/graft. [12] This recognition occurs due to the major histocompatibility complex (MHC), which are proteins on cell surface that are presented to the T-cell receptor found on T-cells. [13] In humans, this is known as the human leukocyte antigen (HLA) system [13] and over 17,000 HLA alleles or genetic variants have been described such that it is extremely uncommon for any two people to have identical alleles. [14] Other non-HLA proteins, known as minor histocompatibility antigens, do exist but generally are unable to cause acute rejection in and of themselves unless a multitude of non-HLA proteins are mismatched. [15] As such, HLA matching (in addition to matching ABO groups) is critical in preventing acute rejection. [16]

This process of recognition by T-cells can happen directly or indirectly and lead to acute cellular and acute humoral rejection respectively. [6] Direct allorecognition is a phenomenon within transplant immunology where the dendritic cells, which are the body's antigen-presenting cells (APCs), migrate from donor tissue to lymphoid tissue (lymphoid follicles and lymph nodes) in the recipient and present their MHC peptides to recipient lymphocytes. [17] In comparison, indirect allorecognition is more analogous to how foreign antigens are recognized by the immune system. [18] Dendritic cells of the recipient come across peptides from donor tissue whether in circulation, lymphoid tissue, or in donor tissue itself. [18] Since not the result of direct antigen presentation, these may not necessarily be intact MHC molecules but instead other proteins that are deemed different enough from recipient may engender a response. [18] This process leads to the priming of T-cells to respond to the peptides secondarily going forward. [2] A third semi-direct pathway has been described in which recipient APCs present fully intact donor MHCs, [17] yet its relative contribution to acute rejection is not as well understood. [15]

Acute cellular rejection occurs following direct allorecognition of mismatched donor MHC by cytotoxic T-cells that begin to secrete cytokines to recruit more lymphocytes as well as cause apoptosis or cell death directly. [4] [6] The greater the difference in MHC between donor and recipient, the more cytotoxic T-cells are recruited to damage the graft, [6] which may be seen via biopsy in solid organ transplants, with increased lymphocyte infiltration indicative of more severe acute cellular rejection. [15] Acute humoral rejection is a process usually initiated by indirect allorecognition arising from recipient helper T-cells. [6] These helper T-cells have a crucial role in the development of B-cells that can create donor-specific antibodies. [4] The antibodies deposit themselves within the donor graft and lead to activation of the complement cascade alongside antibody-mediated cytotoxicity with neutrophils, a type of white blood cell separate from lymphocytes, predominantly infiltrating into tissues. [6]

Barring genetically identical twins, acute rejection is to be expected to some degree. [16] Rates of clinically significant acute rejection that could endanger transplant have decreased significantly with the development of immunosuppressive regimens. Using kidney transplants as an example, rates of acute rejection have declined from >50% in the 1970s to 10-20%. [19] Singular episodes of acute rejection, when promptly treated, should not compromise transplant; however, repeated episodes may lead to chronic rejection. [16]

Chronic rejection

Micrograph showing a glomerulus with changes characteristic of a transplant glomerulopathy. Transplant glomerulopathy is considered a form of chronic antibody-mediated rejection. PAS stain. Transplant glomerulopathy - very high mag.jpg
Micrograph showing a glomerulus with changes characteristic of a transplant glomerulopathy. Transplant glomerulopathy is considered a form of chronic antibody-mediated rejection. PAS stain.

Chronic rejection is an insidious form of rejection that leads to graft destruction over the course of months, but most often years after tissue transplantation. [12] The mechanism for chronic rejection is yet to be fully understood, but it is known that prior acute rejection episodes are the main clinical predictor for the development of chronic rejection. [6] In particular, the incidence increases following severe or persistent acute rejection, whereas acute rejection episodes with return to function back to baseline do not have major effects on graft survival. [20] [21] Chronic rejection is generally thought of as being related to either vascular damage or parenchymal damage with subsequent fibrosis. [22] While it is unknown the exact contribution of the immune system in these processes, the indirect pathway of allorecognition and the associated antibody formation seems to be especially involved. [6]

Chronic rejection has widely varied effects on different organs. At 5 years post-transplant, 80% of lung transplants, 60% of heart transplants and 50% of kidney transplants are affected, while liver transplants are only affected 10% of the time. [20] Therefore, chronic rejection explains long-term morbidity in most lung-transplant recipients, [23] [24] the median survival roughly 4.7 years, about half the span versus other major organ transplants. [25] Airflow obstruction not ascribable to other cause is labeled bronchiolitis obliterans syndrome (BOS), confirmed by a persistent drop—three or more weeks—in forced expiratory volume (FEV1) by at least 20%. [26] First noted is infiltration by lymphocytes, followed by epithelial cell injury, then inflammatory lesions and recruitment of fibroblasts and myofibroblasts, which proliferate and secrete proteins forming scar tissue. [27] A similar phenomenon can be seen with liver transplant wherein fibrosis leads to jaundice secondary to the destruction of bile ducts within the liver, also known as vanishing bile duct syndrome. [28]

Rejection due to non-adherence

One principal reason for transplant rejection is non-adherence to prescribed immunosuppressant regimens. This is particularly the case with adolescent recipients, [29] with non-adherence rates near 50% in some instances. [29]

A pilot study conducted by Michael O. Killian PhD from Florida State University and Dr. Dipankar Gupta from University of Florida published in April 2022 in Pediatric Transplantation [30] studied the acceptability and feasibility of an asynchronous directly observed therapy mobile health application among adolescent heart transplant recipients. Patients in the study utilized emocha Health's digital medication adherence program which included asynchronous video messages and chat messages exchanged with a care team. Patients completing the study achieved a 90.1% adherence rate. The researchers noted that further randomized trials are required to confirm the initial findings. However, the results were very promising considering few options exist to support pediatric patients in taking their medications.

Rejection detection

Diagnosis of acute rejection relies on clinical data—patient signs and symptoms but also calls on laboratory data such as blood or even tissue biopsy. The laboratory pathologist generally seeks three main histological signs: (1) infiltrating T cells, perhaps accompanied by infiltrating eosinophils, plasma cells, and neutrophils, particularly in telltale ratios, (2) structural compromise of tissue anatomy, varying by tissue type transplanted, and (3) injury to blood vessels. Tissue biopsy is restricted, however, by sampling limitations and risks/complications of the invasive procedure. [31] [32] [33] Cellular magnetic resonance imaging (MRI) of immune cells radiolabeled in vivo might—similarly to Gene Expression Profiling (GEP)—offer noninvasive testing. [34] [35]

Rejection treatment

Hyperacute rejection manifests severely and within minutes, and so treatment is immediate: removal of the tissue. Acute rejection is treated with one or several of a few strategies. Despite treatment, rejection remains a major cause of transplant failure. [36] Chronic rejection is generally considered irreversible and poorly amenable to treatment—only retransplant generally indicated if feasible—though inhaled ciclosporin is being investigated to delay or prevent chronic rejection of lung transplants.

Immunosuppressive therapy

A short course of high-dose corticosteroids can be applied, and repeated. Triple therapy adds a calcineurin inhibitor and an anti-proliferative agent. Where calcineurin inhibitors or steroids are contraindicated, mTOR inhibitors are used.

Immunosuppressive drugs:

Antibody-based treatments

Antibody specific to select immune components can be added to immunosuppressive therapy. The monoclonal anti-T cell antibody OKT3, once used to prevent rejection, and still occasionally used to treat severe acute rejection, has fallen into disfavor, as it commonly brings severe cytokine release syndrome and late post-transplant lymphoproliferative disorder. (OKT3 is available in the United Kingdom for named-patient use only.)

Antibody drugs:

Blood transfer

Cases refractory to immunosuppressive or antibody therapy are sometimes treated with photopheresis, or extracorporeal photoimmune therapy (ECP), to remove antibody molecules specific to the transplanted tissue.

Marrow transplant

Bone marrow transplant can replace the transplant recipient's immune system with the donor's, and the recipient accepts the new organ without rejection. The marrow's hematopoietic stem cells—the reservoir of stem cells replenishing exhausted blood cells including white blood cells forming the immune system—must be of the individual who donated the organ or of an identical twin or a clone. There is a risk of graft-versus-host disease (GVHD), however, whereby mature lymphocytes entering with marrow recognize the new host tissues as foreign and destroy them.

Gene therapy

Gene therapy is another method that can be used. In this method, the genes that cause the body to reject transplants would be deactivated. Research is still being conducted, and no gene therapies are being used to date to treat patients. [37] [38] [39] Current research tends to focus[ citation needed ] on Th1 and Th17 which mediate allograft rejection via the CD4 and CD8 T cells. [40]

See also

Related Research Articles

Histocompatibility, or tissue compatibility, is the property of having the same, or sufficiently similar, alleles of a set of genes called human leukocyte antigens (HLA), or major histocompatibility complex (MHC). Each individual expresses many unique HLA proteins on the surface of their cells, which signal to the immune system whether a cell is part of the self or an invading organism. T cells recognize foreign HLA molecules and trigger an immune response to destroy the foreign cells. Histocompatibility testing is most relevant for topics related to whole organ, tissue, or stem cell transplants, where the similarity or difference between the donor's HLA alleles and the recipient's triggers the immune system to reject the transplant. The wide variety of potential HLA alleles lead to unique combinations in individuals and make matching difficult.

<span class="mw-page-title-main">Immunosuppressive drug</span> Drug that inhibits activity of immune system

Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent the activity of the immune system.

Anti-thymocyte globulin (ATG) is an infusion of horse or rabbit-derived antibodies against human T cells and their precursors (thymocytes), which is used in the prevention and treatment of acute rejection in organ transplantation and therapy of aplastic anemia due to bone marrow insufficiency.

<span class="mw-page-title-main">Hematopoietic stem cell transplantation</span> Medical procedure to replace blood or immune stem cells

Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood in order to replicate inside of a patient and to produce additional normal blood cells. It may be autologous, allogeneic or syngeneic.

<span class="mw-page-title-main">Graft-versus-host disease</span> Medical condition

Graft-versus-host disease (GvHD) is a syndrome, characterized by inflammation in different organs. GvHD is commonly associated with bone marrow transplants and stem cell transplants.

<span class="mw-page-title-main">Xenotransplantation</span> Transplantation of cells or tissue across species

Xenotransplantation, or heterologous transplant, is the transplantation of living cells, tissues or organs from one species to another. Such cells, tissues or organs are called xenografts or xenotransplants. It is contrasted with allotransplantation, syngeneic transplantation or isotransplantation and autotransplantation. Xenotransplantation is an artificial method of creating an animal-human chimera, that is, a human with a subset of animal cells. In contrast, an individual where each cell contains genetic material from a human and an animal is called a human–animal hybrid.

<span class="mw-page-title-main">Kidney transplantation</span> Medical procedure

Kidney transplant or renal transplant is the organ transplant of a kidney into a patient with end-stage kidney disease (ESRD). Kidney transplant is typically classified as deceased-donor or living-donor transplantation depending on the source of the donor organ. Living-donor kidney transplants are further characterized as genetically related (living-related) or non-related (living-unrelated) transplants, depending on whether a biological relationship exists between the donor and recipient. The first successful kidney transplant was performed in 1954 by a team including Joseph Murray, the recipient’s surgeon, and Hartwell Harrison, surgeon for the donor. Murray was awarded a Nobel Prize in Physiology or Medicine in 1990 for this and other work. In 2018, an estimated 95,479 kidney transplants were performed worldwide, 36% of which came from living donors.

Alloimmunity is an immune response to nonself antigens from members of the same species, which are called alloantigens or isoantigens. Two major types of alloantigens are blood group antigens and histocompatibility antigens. In alloimmunity, the body creates antibodies against the alloantigens, attacking transfused blood, allotransplanted tissue, and even the fetus in some cases. Alloimmune (isoimmune) response results in graft rejection, which is manifested as deterioration or complete loss of graft function. In contrast, autoimmunity is an immune response to the self's own antigens. Alloimmunization (isoimmunization) is the process of becoming alloimmune, that is, developing the relevant antibodies for the first time.

Tissue typing is a procedure in which the tissues of a prospective donor and recipient are tested for compatibility prior to transplantation. Mismatched donor and recipient tissues can lead to rejection of the tissues. There are multiple methods of tissue typing.

<span class="mw-page-title-main">Minor histocompatibility antigen</span>

Minor histocompatibility antigen are peptides presented on the cellular surface of donated organs that are known to give an immunological response in some organ transplants. They cause problems of rejection less frequently than those of the major histocompatibility complex (MHC). Minor histocompatibility antigens (MiHAs) are diverse, short segments of proteins and are referred to as peptides. These peptides are normally around 9-12 amino acids in length and are bound to both the major histocompatibility complex (MHC) class I and class II proteins. Peptide sequences can differ among individuals and these differences arise from SNPs in the coding region of genes, gene deletions, frameshift mutations, or insertions. About a third of the characterized MiHAs come from the Y chromosome. Prior to becoming a short peptide sequence, the proteins expressed by these polymorphic or diverse genes need to be digested in the proteasome into shorter peptides. These endogenous or self peptides are then transported into the endoplasmic reticulum with a peptide transporter pump called TAP where they encounter and bind to the MHC class I molecule. This contrasts with MHC class II molecules's antigens which are peptides derived from phagocytosis/endocytosis and molecular degradation of non-self entities' proteins, usually by antigen-presenting cells. MiHA antigens are either ubiquitously expressed in most tissue like skin and intestines or restrictively expressed in the immune cells.

A panel-reactive antibody (PRA) is a group of antibodies in a test serum that are reactive against any of several known specific antigens in a panel of test leukocytes or purified HLA antigens from cells. It is an immunologic metric routinely performed by clinical laboratories on the blood of people awaiting organ transplantation.

Human leukocyte antigens (HLA) began as a list of antigens identified as a result of transplant rejection. The antigens were initially identified by categorizing and performing massive statistical analyses on interactions between blood types. This process is based upon the principle of serotypes. HLA are not typical antigens, like those found on surface of infectious agents. HLAs are alloantigens, they vary from individual to individual as a result of genetic differences. An organ called the thymus is responsible for ensuring that any T-cells that attack self proteins are not allowed to live. In essence, every individual's immune system is tuned to the specific set of HLA and self proteins produced by that individual; where this goes awry is when tissues are transferred to another person. Since individuals almost always have different "banks" of HLAs, the immune system of the recipient recognizes the transplanted tissue as non-self and destroys the foreign tissue, leading to transplant rejection. It was through the realization of this that HLAs were discovered.

Alloantigen recognition refers to immune system recognition of genetically encoded polymorphisms among the genetically distinguishable members of same species. Post-transplant recognition of alloantigens occurs in secondary lymphoid organs. Donor specific antigens are recognized by recipient’s T lymphocytes and triggers adaptive pro-inflammatory response which consequently leads to rejection of allogenic transplants. Allospecific T lymphocytes may be stimulated by three major pathways: direct recognition, indirect recognition or semidirect recognition. The pathway involved in specific cases is dictated by intrinsic and extrinsic factors of allograft and directly influence nature and magnitude of T lymphocytes mediated immune response. Furthermore, variant tissues and organs such as skin or cornea or solid organ transplants can be recognized in different pathways and therefore are rejected in different fashion.

<span class="mw-page-title-main">Transplant glomerulopathy</span> Medical condition

Transplant glomerulopathy(TG) is a morphologic lesion of renal allografts that is histologically identified by glomerular basement membrane (GBM) duplication and/or multilayering. Proteinuria, hypertension, and deteriorating graft function are the hallmarks of TG.

Graft-versus-tumor effect (GvT) appears after allogeneic hematopoietic stem cell transplantation (HSCT). The graft contains donor T cells that can be beneficial for the recipient by eliminating residual malignant cells. GvT might develop after recognizing tumor-specific or recipient-specific alloantigens. It could lead to remission or immune control of hematologic malignancies. This effect applies in myeloma and lymphoid leukemias, lymphoma, multiple myeloma and possibly breast cancer. It is closely linked with graft-versus-host disease (GvHD), as the underlying principle of alloimmunity is the same. CD4+CD25+ regulatory T cells (Treg) can be used to suppress GvHD without loss of beneficial GvT effect. The biology of GvT response is still not fully understood but it is probable that the reaction with polymorphic minor histocompatibility antigens expressed either specifically on hematopoietic cells or more widely on a number of tissue cells or tumor-associated antigens is involved. This response is mediated largely by cytotoxic T lymphocytes (CTL) but it can be employed by natural killers as separate effectors, particularly in T-cell-depleted HLA-haploidentical HSCT.

<span class="mw-page-title-main">Intestine transplantation</span> Surgical replacement of the small intestine

Intestine transplantation is the surgical replacement of the small intestine for chronic and acute cases of intestinal failure. While intestinal failure can oftentimes be treated with alternative therapies such as parenteral nutrition (PN), complications such as PN-associated liver disease and short bowel syndrome may make transplantation the only viable option. One of the rarest type of organ transplantation performed, intestine transplantation is becoming increasingly prevalent as a therapeutic option due to improvements in immunosuppressive regimens, surgical technique, PN, and the clinical management of pre and post-transplant patients.

Thymoglobulin is an anti-human thymocyte immunoglobulin preparation made of purified polyclonal antibodies derived from rabbits. While these antibodies have a variety of specificities, their main mechanism of immunosuppression is through depletion of T cells. Thymoglobulin is currently approved for clinical use in Europe and the United States for renal allograft rejection, prevention of graft-vs.-host disease, and conditions involving bone marrow failure, including aplastic anemia and has additional off-label uses.

Complement-dependent cytotoxicity (CDC) is an effector function of IgG and IgM antibodies. When they are bound to surface antigen on target cell, the classical complement pathway is triggered by bonding protein C1q to these antibodies, resulting in formation of a membrane attack complex (MAC) and target cell lysis.

T-cell depletion (TCD) is the process of T cell removal or reduction, which alters the immune system and its responses. Depletion can occur naturally or be induced for treatment purposes. TCD can reduce the risk of graft-versus-host disease (GVHD), which is a common issue in transplants. The idea that TCD of the allograft can eliminate GVHD was first introduced in 1958. In humans the first TCD was performed in severe combined immunodeficiency patients.

<span class="mw-page-title-main">Shimon Slavin</span> Israeli professor of medicine

Shimon Slavin is an Israeli professor of medicine. Slavin pioneered the use of immunotherapy mediated by allogeneic donor lymphocytes and innovative methods for stem cell transplantation for the cure of hematological malignancies and solid tumors, and using hematopoietic stem cells for induction of transplantation tolerance to bone marrow and donor allografts.

References

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