Immunology of Transplant Rejection

Author: Prashant Malhotra, MBBS; Chief Editor: Ron Shapiro, MD more...

Updated: Apr 16, 2013

Overview

Transplantation is the act of transferring cells, tissues, or organs from one site to another. The malfunction of an organsystem can be corrected with transplantation of an organ (eg, kidney, liver, heart, lung, or pancreas) from a donor.However, the immune system remains the most formidable barrier to transplantation as a routine medical treatment.The immune system has developed elaborate and effective mechanisms to combat foreign agents. Thesemechanisms are also involved in the rejection of transplanted organs, which are recognized as foreign by therecipient's immune system.

Understanding these mechanisms is important, as it aids in understanding the clinical features of rejection and, hence,in making an early diagnosis and delivering appropriate treatment. Knowledge of these mechanisms is also critical indeveloping strategies to minimize rejection and in developing new drugs and treatments that blunt the effects of theimmune system on transplanted organs, thereby ensuring longer survival of these organs.

While African Americans have historically had inferior outcomes after renal transplantation, a recent analysis suggests

that this holds true for younger recipients but not for older recipients.[1]

For more information on various transplantation procedures, see Transplantation journal and the Medscape resourcecenters for Heart & Lung Transplant, Kidney & Pancreas Transplant, and Liver & Intestine Transplant.

History

In 1944, Medawar showed that skin allograft rejection is a host versus graft response. Mitchison later demonstratedthe cell-mediated features of this response. The first successful identical twin transplant of a human kidney wasperformed by Joseph E. Murray in 1954 in Boston, followed by the first successful liver transplant by Dr. Thomas E.Starzl in 1967, the first heart transplantation by Christian Barnard in 1967, and the first successful bone marrowtransplant by E. Donnall Thomas in 1968. Schwartz and Dameshek, in 1959, showed that 6-mercaptopurine wasimmunosuppressive in rats, ushering in the era of immunosuppressive drug treatment. Since then, many new andprogressively more selective immunosuppressive agents have been developed. These therapies have enabled thetransplantation of and improved the survival of transplanted organs.

Types of Grafts

The degree of immune response to a graft depends partly on the degree of genetic disparity between the graftedorgan and the host. Xenografts, which are grafts between members of different species, have the most disparity andelicit the maximal immune response, undergoing rapid rejection. Autografts, which are grafts from one part of the bodyto another (eg, skin grafts), are not foreign tissue and, therefore, do not elicit rejection. Isografts, which are graftsbetween genetically identical individuals (eg, monozygotic twins), also undergo no rejection.

Allografts are grafts between members of the same species that differ genetically. This is the most common form oftransplantation. The degree to which allografts undergo rejection depends partly on the degree of similarity orhistocompatibility between the donor and the recipient.

The degree and type of response also vary with the type of the transplant. Some sites, such as the eye and the brain,are immunologically privileged (ie, they have minimal or no immune system cells and can tolerate even mismatchedgrafts). Skin grafts are not initially vascularized and so do not manifest rejection until the blood supply develops. Theheart, kidneys, and liver are highly vascular organs and lead to a vigorous cell mediated response in the host.

Immunobiology of Rejection

Genetic background

TodayNewsReferenceEducationLog InRegister

1 of 8

The antigens responsible for rejection of genetically disparate tissues are called histocompatibility antigens; they areproducts of histocompatibility genes. Histocompatibility antigens are encoded on more than 40 loci, but the lociresponsible for the most vigorous allograft rejection reactions are located on the major histocompatibility complex(MHC).

In humans, the MHC is called the human leukocyte antigen (HLA) system and is located on the short arm ofchromosome 6, near the complement genes. Other antigens cause only weaker reactions, but combinations of severalminor antigens can elicit strong rejection responses. The MHC genes are codominantly expressed, which means thateach individual expresses these genes from both the alleles on the cell surface. Furthermore, they are inherited ashaplotypes or 2 half sets (one from each parent). This makes a person half identical to each of his or her parents withrespect to the MHC complex. This also leads to a 25% chance that an individual might have a sibling who is HLAidentical.

The MHC molecules are divided into 2 classes. The class I molecules are normally expressed on all nucleated cells,whereas the class II molecules are expressed only on the professional antigen-presenting cells (APCs), such asdendritic cells, activated macrophages, and B cells. The physiological function of the MHC molecules is to presentantigenic peptides to T cells, since the T lymphocytes only recognize antigen when presented in a complex with anMHC molecule. The class I molecules are responsible for presenting antigenic peptides from within the cell (eg,antigens from the intracellular viruses, tumor antigens, self-antigens) to CD8 T cells. The class II molecules presentextracellular antigens such as extracellular bacteria to CD4 T cells.

Mechanisms of rejection

The immune response to a transplanted organ consists of both cellular (lymphocyte mediated) and humoral (antibodymediated) mechanisms. Although other cell types are also involved, the T cells are central in the rejection of grafts.The rejection reaction consists of the sensitization stage and the effector stage.

Sensitization stage

In this stage, the CD4 and CD8 T cells, via their T-cell receptors, recognize the alloantigens expressed on the cells ofthe foreign graft. Two signals are needed for recognition of an antigen; the first is provided by the interaction of the Tcell receptor with the antigen presented by MHC molecules, the second by a costimulatory receptor/ligand interactionon the T cell/APC surface. Of the numerous costimulatory pathways, the interaction of CD28 on the T cell surface withits APC surface ligands, B7-1 or B7-2 (commonly known as CD80 or CD86, respectively), has been studied the

most.[2] In addition, cytotoxic T lymphocyte–associated antigen-4 (CTLA4) also binds to these ligands and provides aninhibitory signal. Other costimulatory molecules include the CD40 and its ligand CD40L (CD154).

Typically, helices of the MHC molecules form the peptide-binding groove and are occupied by peptides derived fromnormal cellular proteins. Thymic or central tolerance mechanisms (clonal deletion) and peripheral tolerancemechanisms (eg, anergy) ensure that these self-peptide MHC complexes are not recognized by the T cells, therebypreventing autoimmune responses.

At least 2 distinct, but not necessarily mutually exclusive, pathways of allorecognition exist, the direct and indirectpathways. Each leads to the generation of different sets of allospecific T cell clones.

Direct pathway

In the direct pathway, host T cells recognize intact allo-MHC molecules on the surface of the donor or stimulator cell.Mechanistically, host T cells see allo-MHC molecule + allo-peptide as being equivalent in shape to self-MHC + foreignpeptide and, hence, recognize the donor tissue as foreign. This pathway is presumably the dominant pathway involvedin the early alloimmune response.

The transplanted organ carries a variable number of passenger APCs in the form of interstitial dendritic cells. SuchAPCs have a high density of allo-MHC molecules, and are capable of directly stimulating the recipient's T cells. Therelative number of T cells that proliferate on contact with allogeneic or donor cells is extraordinarily high as comparedwith the number of clones that target antigen presented by self-APC. Thus, this pathway is important in acuteallorejection.

Indirect pathway

In the indirect pathway, T cells recognize processed alloantigen presented as peptides by self-APCs. Secondaryresponses such as those that occur in chronic or late acute rejection are associated with T cell proliferative responsesto a more variable repertoire, including peptides that were previously immunologically silent. Such a change in thepattern of T cell responses has been termed epitope switching or spreading.

A link between self-MHC + allopeptide-primed T cells and the development of acute vascular type rejection has beendemonstrated to be mediated in part by accelerated alloantibody production. In addition, chronic allograft vasculopathymay be mediated by T cells primed by the indirect pathway.

Molecular mechanisms of T cell activation

During T cell activation, membrane-bound inositol phospholipid is hydrolyzed into diacylglycerol (DAG) and IP3. Thisincreases the cytoplasmic calcium. The elevation in calcium promotes the formation of calcium-calmodulin complexes

2 of 8

that activate a number of kinases as well as protein phosphatase IIB or calcineurin. Calcineurin dephosphorylatescytoplasmic nuclear factor of activated T cells (NFAT), permitting its translocation to the nucleus, where it binds to theIL-2 promoter sequence and then stimulates transcription of IL-2 mRNA. Numerous other intracellular events, includingprotein kinase C (PKC) activation by DAG and activation of nuclear factor kappa B (NFkB) also occur at the molecularlevel.

Effector stage

Alloantigen-dependent and independent factors contribute to the effector mechanisms. Initially, nonimmunologic "injuryresponses" (ischemia) induce a nonspecific inflammatory response. Because of this, antigen presentation to T cells isincreased as the expression of adhesion molecules, class II MHC, chemokines, and cytokines is upregulated. It alsopromotes the shedding of intact, soluble MHC molecules that may activate the indirect allorecognition pathway. Afteractivation, CD4-positive T cells initiate macrophage-mediated delayed type hypersensitivity (DTH) responses andprovide help to B cells for antibody production.

Various T cells and T cell-derived cytokines such as IL-2 and IFN-γ are upregulated early after transplantation. Later,ß-chemokines like RANTES (regulated upon activation, normal T cell expressed and secreted), IP-10, and MCP-1 areexpressed, and this promotes intense macrophage infiltration of the allograft. IL-6, TNF-α, inducible nitric oxidesynthase (iNOS) and growth factors, also play a role in this process. The growth factors, including TGF-ß andendothelin, cause smooth muscle proliferation, intimal thickening, interstitial fibrosis, and, in the case of the kidney,glomerulosclerosis.

Endothelial cells activated by T cell–derived cytokines and macrophages express class II MHC, adhesion molecules,and costimulatory molecules. These can present antigen and thereby recruit more T cells, amplifying the rejectionprocess. CD8-positive T cells mediate cell-mediated cytotoxicity reactions either by delivering a "lethal hit" or,alternatively, by inducing apoptosis.

Apoptosis

The final common pathway for the cytolytic processes is triggering of apoptosis in the target cell.[3] After activation of

the CTLs, they form cytotoxic granules that contain perforin and granzymes.[3] At the time of target cell identificationand engagement, these granules fuse with the effector cell membrane and extrude the content into the immunologicalsynapse. By a yet unknown mechanism, the granzymes are inserted into the target cell cytoplasm where granzyme Bcan trigger apoptosis through several different mechanisms, including direct cleavage of procaspase-3 and indirectactivation of procaspase-9. This has been shown to play the dominant role in apoptosis induction in allograft rejection.

Alternatively, CD8-positive CTLs can also use the Fas-dependent pathway to induce cytolysis and apoptosis. The Faspathway is also important in limiting T cell proliferation in response to antigenic stimulation; this is known as fratricidebetween activated CTLs. Cell-mediated cytotoxicity has been shown to play an important role in acute, although notchronic, allograft rejection.

Role of natural killer cells

The natural killer (NK) cells are important in transplantation because of their ability to distinguish allogenic cells from

self and their potent cytolytic effector mechanisms.[4] These cells can mount a maximal effector response without anyprior immune sensitization. Unlike T and B cells, NK cells are activated by the absence of MHC molecules on thesurface of target cells (“missing self” hypothesis). The recognition is mediated by various NK inhibitory receptorstriggered by specific alleles of MHC class I antigens on cell surfaces.

In addition, they also possess stimulatory receptors, which are triggered by antigens on nonself cells. These effectorresponses include both cytokine release and direct toxicity mediated through perforin, granzymes, Fas ligand (FasL),and TNF-related apoptosis-inducing ligand (TRAIL). Through this “double negative” mode of activation, they arethought to play a role in the rejection of both bone marrow and transplantable lymphomas in animal models.

NK cells also provide help to CD28-positive host T cells, thereby promoting allograft rejection.[5] Their importance inthe field of bone marrow transplants has been recognized for years. In humans, their graft-versus-host alloresponsehas been used for its potent graft-versus-leukemia effect and has contributed to an increase in the rate of sustainedremission in patient with acute myelogenous leukemia.

NK cells are now being recognized as active participants in the acute and chronic rejection of solid tissue grafts.[4]

Recent studies have indicated that NK cells are present and activated following infiltration into solid organ allografts.[4]

They may regulate cardiac allograft outcomes. Studies have also shown that humans with killer cellimmunoglobulin-like receptors that are inhibited by donor MHC have a decreased risk of liver transplant rejection. Incases of renal transplantation, these cells are not suppressed by the current immunosuppressive regimens.

Role of innate immunity

Although T cells have a critical role in acute rejection, the up-regulation of proinflammatory mediators in the allograft isnow recognized to occur before the T cell response; this early inflammation following engraftment is due to the innateresponse to tissue injury independent of the adaptive immune system. Several recent studies have examined the roleof Toll-like receptor (TLR) agonists and TLR signals in allorecognition and rejection.

3 of 8

These innate mechanisms alone do not appear sufficient to lead to graft rejection itself. However, they are importantfor optimal adaptive immune responses to the graft and may play a major role in resistance to tolerance induction. Thedevelopment of methods to blunt innate immune responses, which has potential implications for a wide variety ofdiseases, is likely to have a significant impact on transplantation, as well.

Clinical Stages of Rejection

Hyperacute rejection

In hyperacute rejection, the transplanted tissue is rejected within minutes to hours because vascularization is rapidlydestroyed. Hyperacute rejection is humorally mediated and occurs because the recipient has preexisting antibodiesagainst the graft, which can be induced by prior blood transfusions, multiple pregnancies, prior transplantation, orxenografts against which humans already have antibodies. The antigen-antibody complexes activate the complementsystem, causing massive thrombosis in the capillaries, which prevents the vascularization of the graft. The kidney ismost susceptible to hyperacute rejection; the liver is relatively resistant, possibly because of its dual blood supply, butmore likely because of incompletely understood immunologic properties.

Acute rejection

Acute rejection manifests commonly in the first 6 months after transplantation.

Acute cellular rejection

Acute cellular rejection is mediated by lymphocytes that have been activated against donor antigens, primarily in thelymphoid tissues of the recipient. The donor dendritic cells (also called passenger leukocytes) enter the circulation andfunction as antigen-presenting cells (APCs).

Humoral rejection

Humoral rejection is form of allograft injury and subsequent dysfunction, primarily mediated by antibody andcomplement. It can occur immediately posttransplantation (hyperacute) or during the first week. The antibodies areeither preformed antibodies or represent antidonor antibodies that develop after transplantation. Proteinuria isassociated with donor-specific antibody detection and is likely to be an important factor that determines rapidglomerular filtration rate decline and earlier graft failure in patients developing de novo HLA antibodies.[6]

The presence of even low levels of donor-specific antibodies that may not be detected by complement-dependent

cytotoxic and flow cytometry crossmatches have been shown to be associated with inferior renal allograft outcomes.[7]

These patients may require augmented immunosuppression.

The classic pathway inactive product C4d has been shown to be deposited in the peritubular capillaries (PTC), andimmune detection of this product in renal allograft biopsies is used in diagnosis of antibody-mediated rejection.However, one study has demonstrated that there is a substantial fluctuation in the C4d Banoff scores in the first year

posttransplant, and this may reflect the dynamic and indolent nature of the humoral process.[8] Thus, C4d by itself maynot be a sufficiently sensitive indicator, and microvascular inflammation with detection of donor-specific antibodies maybe more useful in diagnosing humoral rejection.

Chronic rejection

Chronic rejection develops months to years after acute rejection episodes have subsided. Chronic rejections are bothantibody- and cell-mediated. The use of immunosuppressive drugs and tissue-typing methods has increased thesurvival of allografts in the first year, but chronic rejection is not prevented in most cases.

Chronic rejection appears as fibrosis and scarring in all transplanted organs, but the specific histopathological picturedepends on the organ transplanted. In heart transplants, chronic rejection manifests as accelerated coronary arteryatherosclerosis. In transplanted lungs, it manifests as bronchiolitis obliterans. In liver transplants, chronic rejection ischaracterized by the vanishing bile duct syndrome. In kidney recipients, chronic rejection (called chronic allograftnephropathy) manifests as fibrosis and glomerulopathy. The following factors increase the risk of chronic rejection:

Previous episode of acute rejectionInadequate immunosuppressionInitial delayed graft functionDonor-related factors (eg, old age, hypertension)Reperfusion injury to organLong cold ischemia timeRecipient-related factors (eg, diabetes, hypertension, hyperlipidemia)Posttransplant infection (eg, cytomegalovirus [CMV])

Transplant Tolerance and Minimizing Rejection

Rejection cannot be completely prevented; however, a degree of immune tolerance to the transplant does develop.

4 of 8

Several concepts have been postulated to explain the development of partial tolerance. They include clonal deletionand the development of anergy in donor specific lymphocytes, development of suppressor lymphocytes, or factorsthat down-regulate the immune response against the graft. Other hypotheses include the persistence of donor-deriveddendritic cells in the recipient that promote an immunologically mediated chimeric state between the recipient and thetransplanted organ.

Tissue typing or crossmatching is performed prior to transplantation to assess donor-recipient compatibility for humanleukocyte antigen (HLA) and ABO blood group. These tests include the following:

The ABO blood group compatibility is tested first because incompatibility between the blood groups leads torapid rejection.In the lymphocytotoxicity assay, patient sera are tested for reactivity with donor lymphocytes. A positivecrossmatch is a contraindication to transplantation because of the risk of hyperacute rejection. This is usedmainly in kidney transplantation.Panel-reactive antibody (PRA) screens the serum of a patient for lymphocytic antibodies against a random cellpanel. Patients with prior transfusions, transplants, or pregnancies may have a high degree of sensitization andare less likely to have a negative crossmatch with a donor. A reduced risk of sensitization at the time of secondtransplant has been observed when using more potent immunosuppression with rabbit antithymocyte globulin,tacrolimus, and mycophenolate mofetil/sodium for nonsensitized primary kidney or kidney/pancreas transplant

patients.[9]

Mixed lymphocyte reaction (MLR) can be used to assess the degree of major histocompatibility complex(MHC) class I and class II compatibility. However, it is not a rapid test and can be used only in cases involvingliving related donors. It is rarely used at present.

Immunosuppression

Initially, radiation and chemicals were used as nonselective immunosuppressive agents. In the late 1950s and 1960s,the agents 6-mercaptopurine and azathioprine were used in conjunction with steroids. Newer immunosuppressiveagents have since been developed; they are more effective, more selective, and less toxic and have made possiblethe advances in the field of transplantation.

Recent adverse experience with medications including rofecoxib, erythropoietin, and rosiglitazone, even after theirapproval, has resulted in increased safety measures, which address perceived deficits in the system for drug approvaland postmarketing safety. Legislation has enabled the US Food and Drug Administration (FDA) to legally enforceintroduced risk evaluation and mitigation strategies and postmarketing requirements.[10]

Immunosuppressive drugs are used in 2 phases: the initial induction phase, which requires much higher doses ofthese drugs, and the later maintenance phase. Immunosuppressive agents in current use include the following:

Immunophilin-binding agents

The available immunophilin-binding agents are cyclosporine and tacrolimus. These agents are calcineurin inhibitors;they primarily suppress the activation of T lymphocytes by inhibiting the production of cytokines, specifically IL-2. Theyare associated with numerous toxicities that are often dose-dependent. Nephrotoxicity occurs with both the drugs.Hirsutism, gingival hypertrophy, hypertension, and hyperlipidemia develop more often with cyclosporine thantacrolimus. (Click here to complete a Medscape CME activity on hirsutism.) Potential drug interactions are alsoimportant to recognize.

Tacrolimus is a macrolide lactone antibiotic produced by the soil fungus Streptomyces tsukubaensis. It binds to adifferent intracellular protein (FKBP-12) than cyclosporine but has the same mechanism of action. Neurotoxicity,alopecia, and posttransplant diabetes mellitus develop more frequently with tacrolimus than with cyclosporine.

Conversion from brand name to generic tacrolimus is routinely feasible, but it requires close monitoring of tacrolimuslevels.[11]

Mammalian target of rapamycin (mTOR) inhibitors

Sirolimus is a macrocyclic antibiotic produced by fermentation of Streptomyces hygroscopicus. It binds to FKBP-12and presumably modulates the activity of the mTOR inhibitor, which inhibits IL-2–mediated signal transduction andresults in T- and B-cell cycle arrest in the G1-S phase. Sirolimus is associated with numerous adverse effects, such asleukopenia, thrombocytopenia, anemia, hypercholesterolemia, and hypertriglyceridemia. It has also been associatedwith mucositis, delayed wound healing, lymphocele formation, pneumonitis, and prolonged delayed graft function.

Antiproliferative agents

Azathioprine and mycophenolate mofetil (MMF) are the agents commonly used in this category. Other antiproliferativeagents, such as cyclophosphamide and, more recently, leflunomide, have also been used.

Antiproliferative agents inhibit DNA replication and suppress B- and T-cell proliferation. MMF is an organic syntheticderivative of the natural fermentation product mycophenolic acid (MPA) that causes noncompetitive reversible

5 of 8

inhibition of inosine monophosphate dehydrogenase. This interferes with purine synthesis. Adverse effects of MMFare nausea, diarrhea, leukopenia, and thrombocytopenia. Invasive CMV infection has been sometimes associated withMMF. The introduction of MMF has been shown to be associated with improvement or stabilization of renal function,even several years after transplantation.[12]

Antibodies

Two antibodies that are IL-2 receptor antagonists (basiliximab and daclizumab) are FDA-approved for kidneytransplantation induction. Antilymphocyte globulin, such as the monoclonal antibody muromonab-CD3, and thepolyclonal antibodies, antithymocyte globulins derived from either equine or rabbit sources, are approved for thetreatment of rejection. They also have been used as induction agents at some transplantation centers.

Antibodies interact with lymphocyte surface antigens, depleting circulating thymus-derived lymphocytes and interferingwith cell-mediated and humoral immune responses. Lymphocyte depletion also occurs either by complement-dependent lysis in the intravascular space or by opsonization and subsequent phagocytosis by macrophages.Adverse effects such as fever, chills, thrombocytopenia, leukopenia, and headache typically occur with the first fewdoses.

Corticosteroids

Steroids have been the cornerstone of immunosuppression and are still used. However, the newer regimens are tryingto minimize the use of steroids and thereby avoid the adverse effects that are associated with them. Steroids are stillimportant in treating episodes of acute rejection.

Future Therapies

Many new agents are designed to interfere with secondary signaling, and this may aid in induction of tolerance.

Monoclonal antibodies to B7-1 (CD80) and B7-2 (CD86) have been developed to block T-cell CD28 activation andproliferation responses. In a recent trial, one of these antibodies, belatacept, did not appear to be inferior tocyclosporine as a means of preventing acute rejection after renal transplantation.

Studies involving the humanized anti-C5 antibody, eculizumab, have demonstrated the effects of a new antibody

therapy on the prevention of antibody-mediated rejection in highly sensitized patients who undergo transplantation.[13]

Cytotoxic T lymphocyte antigen 4 immunoglobulin (CTLA4Ig) can simultaneously inhibit B7-1 and B7-2 interaction withCD28 and has been used successfully in animal models, demonstrating a beneficial effect on chronic allograftrejection.

Other antibodies targeting CD28 are also in development.

Monoclonal anti-CD45-RB, leflunomide, FK778, FTY720, alemtuzumab (anti-CD52 antibody), and rituximab are someof the other agents in different phases of evaluation.

Natural killer (NK) cell inactivation or depletion also harbors the promise that it may improve the long-term outcome oftransplanted organs.

The use of any immunosuppressive drug requires a balance between the risk of loss of transplanted organ and thetoxicity of the agent. The goal is to balance an appropriate level of immunosuppression with the long-term risks, whichinclude development of infections, cancer, and metabolic complications.

Contributor Information and DisclosuresAuthorPrashant Malhotra, MBBS Assistant Professor of Medicine, Division of Infectious Diseases, Department ofMedicine, LIJ School of Medicine at Hofstra University; Attending Physician, Division of Infectious Diseases,Department of Internal Medicine, North Shore-Long Island Jewish Health System

Prashant Malhotra, MBBS is a member of the following medical societies: American College of Physicians,Infectious Diseases Society of America, and Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Coauthor(s)Shruti Malu, PhD Post-doctoral Fellow, Mount Sinai School of Medicine

Disclosure: Nothing to disclose.

Sandip Kapur, MD, FACS Associate Professor, Department of Surgery, Weill Medical College of CornellUniversity, Chief, Division of Transplant Surgery, New York Presbyterian Hospital-Weill Cornell Medical Center

Sandip Kapur, MD, FACS is a member of the following medical societies: American College of Surgeons,

6 of 8

American Society of Transplant Surgeons, Association for Academic Surgery, and Society of Critical Care Medicine

Disclosure: Nothing to disclose.

Specialty Editor BoardFrancisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center Collegeof Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Debra L Sudan, MD Professor of Surgery, Chief, Abdominal Transplant Surgery, Vice Chair of ClinicalOperations, Department of Surgery, Duke University School of Medicine

Debra L Sudan, MD is a member of the following medical societies: Alpha Omega Alpha, American College ofSurgeons, American Society of Transplant Surgeons, American Society of Transplantation, American SurgicalAssociation, Association for Academic Surgery, Association of Women Surgeons, Association of WomenSurgeons, International Liver Transplantation Society, Nebraska Medical Association, Society for Surgery of theAlimentary Tract, and Society of University Surgeons

Disclosure: Nothing to disclose.

Chief EditorRon Shapiro, MD Professor of Surgery, Robert J Corry Chair in Transplantation Surgery, Director, Kidney,Pancreas, and Islet Transplantation, Thomas E Starzl Transplantation Institute, University of Pittsburgh MedicalCenter

Ron Shapiro, MD is a member of the following medical societies: American College of Surgeons, American Societyof Transplant Surgeons, American Society of Transplantation, American Surgical Association, Association forAcademic Surgery, Central Surgical Association, International Pediatric Transplant Association, Society ofUniversity Surgeons, and Transplantation Society

Disclosure: Brystol Meyer Squibb StemCell Data Monitoring Committee Consulting fee Review panel membership;Stem Cells, Inc Consulting fee Review panel membership; Up To Date contracted Author; Novartis HonorariaConsulting; Genentech/Valcyte Honoraria Consulting

References

Schold JD, Srinivas TR, Braun WE, Shoskes DA, Nurko S, Poggio ED. The relative risk of overall graft lossand acute rejection among African American renal transplant recipients is attenuated with advancing age. ClinTransplant. Sep 2011;25(5):721-30. [Medline].

1.

Clarkson MR, Sayegh MH. T-cell costimulatory pathways in allograft rejection and tolerance. Transplantation.Sep 15 2005;80(5):555-63. [Medline].

2.

Krupnick AS, Kreisel D, Popma SH, et al. Mechanism of T cell-mediated endothelial apoptosis.Transplantation. Sep 27 2002;74(6):871-6. [Medline].

3.

Kitchens WH, Uehara S, Chase CM, Colvin RB, Russell PS, Madsen JC. The changing role of natural killercells in solid organ rejection and tolerance. Transplantation. March 2006;81(6):811-7. [Medline].

4.

McNerney ME, Lee KM, Zhou P, Molinero L, Mashayekhi M, Guzior D, et al. Role of natural killer cell subsetsin cardiac allograft rejection. Am J Transplant. March 2006;6(3):505-13. [Medline].

5.

Fotheringham J, Angel C, Goodwin J, Harmer AW, McKane WS. Natural history of proteinuria in renaltransplant recipients developing de novo human leukocyte antigen antibodies. Transplantation. May 152011;91(9):991-6. [Medline].

6.

Willicombe M, Brookes P, Santos-Nunez E, et al. Outcome of patients with preformed donor-specificantibodies following alemtuzumab induction and tacrolimus monotherapy. Am J Transplant. Mar2011;11(3):470-7. [Medline].

7.

Loupy A, Hill GS, Suberbielle C, Charron D, Anglicheau D, Zuber J, et al. Significance of C4d Banff scores inearly protocol biopsies of kidney transplant recipients with preformed donor-specific antibodies (DSA). Am JTransplant. Jan 2011;11(1):56-65. [Medline].

8.

Dawson KL, Patel SJ, Xu J, Knight RJ, Gaber AO. Effect of immunosuppression for first kidney orkidney/pancreas transplant on sensitization at the time of second transplant. Transplantation. Apr 152011;91(7):751-6. [Medline].

9.

Gabardi S, Halloran PF, Friedewald J. Managing Risk in Developing Transplant Immunosuppressive Agents:The New Regulatory Environment. Am J Transplant. Aug 9 2011;[Medline].

10.

7 of 8

Medscape Reference © 2011 WebMD, LLC

Momper JD, Ridenour TA, Schonder KS, Shapiro R, Humar A, Venkataramanan R. The Impact of ConversionFrom Prograf to Generic Tacrolimus in Liver and Kidney Transplant Recipients With Stable Graft Function.Am J Transplant. Jun 30 2011;[Medline].

11.

Meier-Kriesche HU, Merville P, Tedesco-Silva H, et al. Mycophenolate Mofetil Initiation in Renal TransplantPatients at Different Times Posttransplantation: The TranCept Switch Study. Transplantation. May 152011;91(9):984-990. [Medline].

12.

Stegall MD, Diwan T, Raghavaiah S, et al. Terminal complement inhibition decreases antibody-mediatedrejection in sensitized renal transplant recipients. Am J Transplant. Nov 2011;11(11):2405-13. [Medline].

13.

Denton MD, Magee CC, Sayegh MH. Immunosuppressive strategies in transplantation. Lancet. Mar 271999;353(9158):1083-91. [Medline].

14.

Donovitch GM. Handbook of Kidney Transplantation. 2nd ed. Philadelphia, Pa: Lippincott Williams & Wilkins;1996.

15.

Hardinger KL, Koch MJ, Brennan DC. Current and future immunosuppressive strategies in renaltransplantation. Pharmacotherapy. Sep 2004;24(9):1159-76. [Medline].

16.

Jukes JP, Wood KJ, Jones ND. Natural killer T cells: a bridge to tolerance or a pathway to rejection?.Transplantation. Sep 27 2007;84(6):679-81. [Medline].

17.

Klein J, Sato A. The HLA system. First of two parts. N Engl J Med. Sep 7 2000;343(10):702-9. [Medline].18.

Klein J, Sato A. The HLA system. Second of two parts. N Engl J Med. Sep 14 2000;343(11):782-6.[Medline].

19.

Kreisel D, Krupnick AS, Gelman AE, et al. Non-hematopoietic allograft cells directly activate CD8+ T cells andtrigger acute rejection: an alternative mechanism of allorecognition. Nat Med. Mar 2002;8(3):233-9. [Medline].

20.

Krieger NR, Emre S. Novel immunosuppressants. Pediatr Transplant. Dec 2004;8(6):594-9. [Medline].21.

Kuby J. Immunology. 3rd ed. New York, NY: WH Freeman & Co; 1997.22.

LaRosa DF, Rahman AH, Turka LA. The innate immune system in allograft rejection and tolerance. JImmunol. 178(12):7503-9. [Medline].

23.

Le Moine A, Goldman M, Abramowicz D. Multiple pathways to allograft rejection. Transplantation. May 152002;73(9):1373-81. [Medline].

24.

Rocha PN, Plumb TJ, Crowley SD, Coffman TM. Effector mechanisms in transplant rejection. Immunol Rev.Dec 2003;196:51-64. [Medline].

25.

Roitt IM, Delves PJ. Roitt's Essential Immunology. 10th ed. Ames, IA: Blackwell Publishing; 2001.26.

Sayegh MH, Turka LA. The role of T-cell costimulatory activation pathways in transplant rejection. N Engl JMed. Jun 18 1998;338(25):1813-21. [Medline].

27.

Schwartz JC, Zhang X, Fedorov AA, et al. Structural basis for co-stimulation by the human CTLA-4/B7-2complex. Nature. Mar 29 2001;410(6828):604-8. [Medline].

28.

Starzl TE, Zinkernagel RM. Transplantation tolerance from a historical perspective. Nat Rev Immunol. Dec2001;1(3):233-9. [Medline].

29.

Uehara S, Chase CM, Kitchens WH, et al. NK cells can trigger allograft vasculopathy: the role of hybridresistance in solid organ allografts. J Immunol. Sep 1 2005;175(5):3424-30. [Medline].

30.

8 of 8