The Immunology of Transplantation

Introduction

Solid organ transplant requires the removal of an organ from one individual, the donor, and its placement in the recipient. Whether the donor is living or deceased, this process inevitably requires a temporary cessation of circulation and hence oxygenation, with attendant cellular dysfunction and damage. Thus when the blood supply is restored to the allograft in the recipient, and the recipient’s immune system can access the transplant, there are broadly two main stimuli that may be recognized: damage-associated signals that activate the innate immune system, and differences in cell surface molecules (such as human leukocyte antigens [HLA] or blood group antigens) between donor and recipient that can activate the adaptive immune system. In the past 50 years, the increased understanding of cellular adaptive immunity has transformed our ability to suppress this arm of the immune system, such that T cell-mediated rejection (TCMR) is now uncommon, occurring in less than 20% of kidney transplant recipients, for example. However, the control of innate and humoral adaptive immunity remains challenging, and efforts to achieve this will need to be underpinned by a greater understanding of the basic biology of these important systems. Of note, attempts to understand the immune response to an allograft have historically relied on rodent and nonhuman primate models. Although useful, such studies do not always accurately reflect the alloimmune response in humans, and there is an increasing emphasis on the need for experimental medicine studies in transplantation to enable advances in genomic, transcriptomic, and proteomic technologies to be harnessed toward this goal. In this chapter, we will provide a description of the various arms of the immune system and consider how they contribute to the immune response to transplanted organs ( Fig. 2.1 ).

Fig. 2.1, Timeline of allograft rejection.

Activation of the Immune System Peritransplant

During the process of organ retrieval and reimplantation, there is an inevitable period of ischemia. The cessation of oxygen supply renders the cells unable to generate sufficient energy to continue homeostatic processes that maintain cellular integrity, leading to damage or even death of some cells. This cellular damage or death is associated with the release of molecules that can be detected by both the innate and adaptive immune system. During organ reperfusion, it is the innate immune system that is principally activated. This ancient system includes a soluble arm—the complement system and a variety of opsonins that have evolved to facilitate pathogen recognition, for example, C-reactive protein (CRP), complement activation products (C3b), natural immunoglobulin (Ig)M antibody, and a cellular arm, composed of phagocytes and innate lymphoid cells, including natural killer (NK) cells.

Damage Signals and their Receptors

The innate immune system has evolved to recognize molecules expressed by pathogens, known as pathogen-associated molecular patterns (PAMPs), including specific carbohydrates, lipopolysaccharide (LPS), flagellin, lipoteichoic acid, and double-stranded ribonucleic acid (RNA). This is achieved by an array of receptors, so-called pattern recognition receptors (PRRs), some of which are surface bound and survey the extracellular environment, and some of which are located within the cell, in the cytoplasm or endosomal compartments ( Fig. 2.2 ). PRRs include cell-associated receptors, such as toll-like receptors (TLRs), retinoic acid inducible gene-1–like receptors, and nucleotide-binding oligomerization domain (NOD)-like receptors, and soluble molecules, including CRP, ficolins, and mannan-binding lectin (MBL). Matzinger first proposed that the immune system may have the capacity to respond to damage signals, even in the absence of microbes—the danger hypothesis—and may have even evolved in response to these stimuli. It is now clear that many cell-damage or death-associated signals (termed danger-associated molecular patterns [DAMPs]) are recognized by the same PRRs that mediate responses to PAMPs. These DAMPs include extracellular adenosine triphosphate (ATP), hyaluronan, uric acid, heat-shock proteins (HSPs), and high-mobility group box 1 (HMGB1). These molecules are normally hidden from the immune system or are derived from degradation products of extracellular matrix components generated during ischemia reperfusion injury (IRI) and inflammation. Similarly, falling intracellular potassium and oxidative stress can act as intracellular danger signals.

Fig. 2.2, Mechanisms of immune sensing and inflammatory cytokine production during sterile inflammation.

Soluble Innate Immunity—Complement

The complement system is a series of protein kinases that are sequentially activated and culminate in the formation of the membrane attack complex (MAC). The MAC comprises complement components C5 to C9, which are inserted into the cell membrane (pathogen or host), disrupting integrity and causing cell lysis ( Fig. 2.3 ). In addition, many proximal complement components may augment the immune response to the allograft.

The complement system may be activated by three pathways: the classical pathway, the alternative pathway, and the MBL pathway. IgM or IgG immune complexes activate the classical pathway, and hence this pathway may become activated during antibody-mediated rejection (see section on B Cell Activation). The alternative pathway is constitutively active and must be controlled by a series of regulatory proteins. The mannose-binding pathway is activated by carbohydrates present on pathogens or by damaged endothelium. The net result of activating any of the three pathways is the formation of a C3 convertase (either C4bC2a or C3bBb), which cleaves C3. The resulting C3b cleaves C5 and activates a final common pathway resulting in MAC formation. Complement activation also leads to the formation of anaphylatoxins (C3a and C5a), which activate neutrophils and mast cells, promoting inflammation. In addition, C3b can opsonize pathogens for uptake by complement receptors CR1 and CR3 on phagocytes and can activate B cells; the latter may promote B cell activation in transplantation.

Because the alternative pathway is continuously activated, effective regulation is critical to prevent inappropriate activation. Regulatory proteins may be circulating or membrane-bound. Circulating inhibitors include C1 esterase inhibitor and factors H and I. Membrane-bound regulatory proteins include membrane cofactor protein (MCP), CD55 (decay accelerating factor [DAF]), and CD59 (protectin). Defects or mutations in complement regulatory proteins can result in severe renal pathology, for example, atypical hemolytic uremic syndrome (HUS), which can recur in the transplanted allograft. The C3 glomerulopathies , including dense deposit disease and type I and III mesangiocapillary glomerulonephritides, are also underpinned by complement mutations. Small case series suggest a recurrence rate of around 60% in the transplanted organ. The C5 inhibitor eculizumab may well have efficacy in both primary and recurrent forms of these diseases.

The endothelial cell damage associated with ischemia-reperfusion injury during transplantation leads to MBL and alternative complement pathway activation. Histologic evidence of complement activation (C3d deposition) is present in animal models and in human kidneys with acute tubular necrosis (ATN). Factor B-deficiency and a factor B-blocking antibody are protective in a murine model of IRI, suggesting alternative pathway involvement. Biopsies in murine and human kidneys with ATN also demonstrate MBL deposition, likely triggered by endogenous ligands expressed by dying cells, and MBL-deficient mice are protected from IRI. Transplantation of a kidney from a C3-deficient mouse into a C3-sufficient recipient results in significant attenuation of IRI, in contrast to the reciprocal transplant, suggesting that local C3 production in the kidney rather than circulating C3 is the major player in IRI. In human kidneys, cold ischemia may alter the methylation state of the C3 promoter, resulting in increased local expression of C3 after reperfusion, which is associated with a diminished graft survival. Silencing of the gene encoding C3 using small interfering RNA (siRNA) has been shown to reduce C3 expression, histologic and biochemical parameters of kidney injury, and mortality in an animal model of IRI. The terminal pathway products C5a and C5b–C9 appear to be critical in mediating cellular injury. A C5-blocking antibody and C5a receptor antagonist have both been shown to abrogate IRI and gene silencing of the C5a receptor also protects mice from IRI. Gene silencing may provide a promising tool in renal transplantation, because siRNA-to-complement components might be applied to the allograft during cold storage, before implantation. Similarly, other strategies to inhibit local complement activation may have utility in limiting allograft IRI. Ongoing clinical trial in renal transplantation to prevent IRI and delayed graft function include the use of C1 esterase inhibitors ( https://clinicaltrials.gov/ct2/show/NCT02134314 ) and the C5 inhibitor eculizumab ( https://clinicaltrials.gov/ct2/show/NCT02145182 ). However, although there was a reduced rate of delayed graft function in a small pediatric trial ( n = 57) using eculizumab in kidney transplantation, there was an unexpectedly high rate of graft loss because of thrombosis in eculizumab-treated subjects, necessitating caution in its future use in this context.

Innate Immunity—Cellular Components

Cellular innate immunity comprises a variety of hematopoietic myeloid and lymphoid cells, often poised within tissues for the rapid nonspecific detection of invading microorganisms and transformed cells. However, innate immunity also encompasses various nonhematopoietic cells, such as the gastrointestinal, respiratory, and urogenital epithelium, which, in addition to forming a physical barrier, also express PRRs and orchestrate local immunity ( Fig. 2.4 ).

Neutrophils

Although often viewed as nonspecific effector cells, granulocytes, such as neutrophils and eosinophils, are likely to play a significant role in transplant pathology through their potent effector functions and rapid recruitment to sites of inflammation during IRI and rejection. It is also increasingly appreciated that there may be tissue-resident populations within a variety of organs.

Neutrophils are the dominant circulating phagocyte in humans, and their recruitment into the graft involves a complex multistep process requiring a series of interactions between the surface of the leukocyte and the endothelial cell or its extracellular matrix. The proteins involved fall into three groups: the selectins, and members of the integrin and Ig superfamilies. Initial interaction and rolling of neutrophils along the endothelium allow the leukocyte to sample the endothelial environment, while maintaining its ability to detach and travel elsewhere. This step is largely controlled by the selectins, although α ₄ integrins may also play a role. Endothelial cells express interleukin (IL)-8 and platelet-activating factor, which induces strong neutrophil adhesion. This interaction leads to signaling to the neutrophil, slowing and arresting the rolling process. Shedding of L-selectin by leukocytes allows their detachment and extravasation. The latter stages of leukocyte transmigration are regulated mainly by the β ₂ integrins and adhesion proteins of the immunoglobulin superfamily.

The expression of adhesion proteins involved in these interactions is upregulated by proinflammatory cytokines. Ischemic damage alone results in increased expression of several cytokines that upregulate the expression of selectins. Other adhesion proteins, such as intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 of the immunoglobulin superfamily and E-selectin (endothelial-specific selectin), are upregulated by cytokines induced by donor brain death and implantation.

After exit from the vasculature, neutrophil PRR engagement by DAMPs can induce the production of reactive oxygen species, hydrolytic enzymes, and cytokines, with graft neutrophilia linked to alloreactive T cell responses and disease activity in mouse models. Neutrophils can also undergo a form of programmed cell death known as NETosis, whereby activated neutrophils form so-called extracellular traps (NETs). These have been observed in human lung transplant recipients and in mouse models of allograft IRI, although how they contribute to inflammation remains controversial. Perhaps less appreciated is the potential role of neutrophils in the resolution of inflammation in alloimmunity: efferocytosis of apoptotic neutrophils leads to the production of antiinflammatory mediators, such as IL-10, while proresolving factors, including lipoxins and resolvins, are important in wound healing and may suppress ongoing rejection.

Macrophages

Tissue-resident macrophages represent the major innate leukocyte population in most tissues. Through their widespread expression of PRRs, these sentinel cells are specialized in antigen phagocytosis and cytokine production, being key drivers of inflammation in numerous settings. During inflammatory conditions, the macrophage pool is further reinforced by recruited monocytes from the bloodstream, with several macrophage- and monocyte-derived cytokines capable of contributing to tissue damage. For example, tumor necrosis factor (TNF)α can drive cellular necroptosis and the concomitant release of intracellular contents and DAMPs, in addition to augmenting angiogenesis, matrix metalloprotease (MMP) production, immune cell activation, and germinal center formation, all with particular importance in the context of transplantation. Furthermore, via production of IL-1β and IL-8, macrophages play a strategic role in the recruitment of neutrophils to inflamed sites through the induction of adhesion molecules on endothelial cells and direct chemotactic activity, respectively.

Endogenous ligands with the capacity to engage macrophage PRRs are generated during transplantation, either through IRI or as a consequence of ongoing rejection. Detection of DAMPs leads to the association of nucleotide-binding domain leucine-rich repeat containing protein (NLRP)3 with apoptosis-associated speck-like protein (ASC), and recruitment of procaspase-1, forming a complex known as the NLRP3 inflammasome ( Fig. 2.3 ). Inflammasome activation results in the cleavage of procaspase-1 to caspase-1, which subsequently cleaves IL-1β and IL-18 from their precursors. Of note, in vitro data suggests that in macrophages, inflammasome activation is a two-step process. First, macrophages must be “primed” by TLR stimuli, resulting in NFγB-dependent pro-IL-1β production and upregulation of NLRP3 expression. A number of DAMPs are thought to signal via TLRs; for example, HMGB1 activates TLR4. The second signal is provided by DAMP receptors, for example the ATP receptor, P2X7R.

IL-1 plays a pivotal role in initiating and amplifying sterile inflammation, as evidenced by experiments showing that mice deficient in the IL-1 receptor (IL-1R) or in the adaptor protein MyD88 (which is required for IL-1R signaling), demonstrate minimal neutrophilic inflammation after challenge with necrotic cells. IL-1β has multiple actions, including stimulation of nonhematopoietic cells to produce the neutrophil chemoattractants chemokine (C-X-C motif) ligand (CXCL)2 (also known as macrophage inflammatory protein [MIP]-2) and CXCL1 (also known as keratinocyte chemoattractant [KC]). DAMPs may also act directly as chemotactic agents for neutrophils. IL-1β also increases the expression of cell adhesion molecules (e.g., ICAM-1 [CD54]) on endothelial cells. ICAM-1 interacts with integrins (CD11 and CD18) on neutrophils and monocytes to promote endothelial adherence and subsequent entry into tissues.

There is a significant body of evidence that suggests that sterile inflammation contributes to the severity of IRI; neutralization of the DAMP HMGB1 with a monoclonal antibody attenuates renal injury after IRI, whereas recombinant HMGB1 exacerbates it. Some DAMPs stimulate TLRs, and mice deficient in TLR-2 and TLR-4 are protected from IRI with a reduction in neutrophil and macrophage infiltration. Furthermore, NLRP3, ASC, and caspase-1 deficient mice are protected from renal ischemic injury. Pharmacologic inhibition of caspase-1 has been shown to reduce renal IRI and may therefore be a viable therapeutic strategy in transplantation. In rodent models, treatment with monoclonal antibodies directed against ICAM-1, CD11a, or CD11b also protect against IRI. In a human phase I trial, ICAM blockade using a murine antibody BIRR1 was associated with a reduction in delayed graft function in renal transplant recipients. However, a randomized controlled trial of anti-ICAM-1 antibody in renal transplantation failed to demonstrate any significant improvement in delayed graft function. Blockade of another adhesion molecule, P-selectin, also attenuates leukocyte recruitment and IRI in rodent models and in humans.

Innate cells may also drive an adaptive alloimmune response. In TCMR, macrophages may act as antigen-presenting cells (APCs), and the IRI-associated inflammation may induce upregulation of major histocompatibility complex (MHC) class II (MHC-II) on resident cells, augmenting their antigen-presenting functions. In antibody-mediated rejection (ABMR), IgG and complement are deposited in peritubular capillaries, facilitating monocyte, macrophage, and neutrophil activation via their Fcγ receptors (FcγR) and complement receptors. Indeed, the presence of neutrophils within peritubular capillaries is one of the diagnostic features of ABMR, and increased numbers of intraglomerular monocytes and macrophages have been observed in C4d+ ABMR. Macrophages may also contribute to chronic ABMR; early macrophage infiltration is predictive of chronic allograft nephropathy and long-term graft survival.

NK Cells and Innate Lymphoid Cells

In the context of organ transplantation, it is increasingly clear that NK cells play a significant role. NK cells are a distinct class of cytotoxic lymphocyte characterized by the production of perforin, granzymes, and IFNγ that play a role as effector cells, lysing sensitive targets according to the presence or absence of specific target antigens. Two subsets of NK cells exist in humans, CD56 ^bright cells and CD56 ^dim cells, with CD56 ^dim NK cells comprising approximately 90% of blood and spleen NK cells. This subset expresses FcγRIIIA (CD16) and undergoes antibody-dependent cell-mediated cytotoxicity (ADCC), the targeted release of cytotoxic molecules in response to FcγR ligation by IgG-opsonized cells. The relevance of ADCC to organ rejection will be discussed in more detail when discussing mechanisms of ABMR. NK cells also express an array of other activating and inhibitory cell surface receptors that dictate cellular activation depending on the microenvironment encountered by the cell. Although the importance of NK cells in bone marrow transplantation has been long established, their role in solid organ transplantation has taken longer to be recognized. Several laboratories using different experimental models found that grafts survive indefinitely in the presence of demonstrable NK effector activity, although more recently CD28-independent rejection in mouse models of transplantation has been shown to be NK dependent and sensitive to blockade of NKG2D. The activating receptor NKG2D is engaged by MHC class I polypeptide-related sequence (MIC) A (MICA) and MICB, that are induced in allografts during acute and chronic rejection. The binding of these ligands to NKG2D activates NK cells to enhance effector functions, whereas the engagement of killer immunoglobulin-like receptors (KIRs) by KIR ligands such as HLA-C (KIR2DL1 and KIR2DL2) and HLA Bw4 (KIR3DL1) generally inhibit function. Genetic studies of donor and recipient HLA-C type (grouped as C1 and C2 depending on polymorphisms at position 77 and 80 and which seem to exhibit differential NK cell inhibition) suggest that long-term outcomes may be influenced by donor or recipient interaction with KIRs. This has also been observed when KIR HLA mismatches are analyzed in HLA-compatible transplantation.

Inhibitory receptor function underlies the phenomenon of responses to “missing self,” which contributes to tumor immunity, the killing of stem cells, and hybrid resistance in experimental models of transplantation.

Beyond NK cells, another class of innate lymphocyte are the recently described “helper” innate lymphoid cells (ILCs). The subject of intense research in the last decade, ILCs are characterized by their similarity to helper T (Th) cell subsets, with the notable absence of somatically recombined antigen-specific receptors or classical lineage markers. ILCs can subdivided into ILC1s, ILC2s, and ILC3s, which mirror Th1, Th2, and Th17 subsets in terms of transcription factor dependency and effector cytokine profile. The phenotype and dynamics of donor and recipient helper ILCs after transplantation remains poorly understood. However, it is likely that the nature of the transplanted organ dictates the relative contribution of ILCs to transplant phenomena: ILCs may be expected to have significant influence on transplanted mucosal tissues, because they are particularly enriched at these sites. For example, the production of homeostatic IL-22 and amphiregulin by ILC3s and ILC2s, respectively, may limit detrimental tissue destruction and reinforce antimicrobial defense at the mucosal epithelium in the gut and lung. Indeed, ILC3-derived IL-22 production has been implicated in reduced disease progression and intestinal tissue damage in murine models of graft-versus-host disease. Conversely, the transition to ILC1-like phenotypes is associated with increased inflammation and may promote early graft dysfunction. Curiously, the absence of ILC reconstitution in severe combined immunodeficiency (SCID) patients after hematopoietic stem cell (HSC) transplantation, including NK cells, was not associated with any overt susceptibility to disease. Therefore more investigation into the precise nature of ILCs within allografts is needed.

Cells at the Interface between Innate and Adaptive Immunity

Although sufficient for initial protection against most microorganisms and sterile insults, innate immunity plays a crucial role in shaping adaptive immune responses according to the context in which antigen is encountered. Indeed, complex mechanisms have evolved to ensure optimal targeting of different effector mechanisms against viruses, bacteria, fungi, protozoa, and multicellular parasites, while maintaining immunologic tolerance toward innocuous self and foreign antigens.

A critical class of innate immune cell mediating this cross-talk between innate and adaptive immunity is the dendritic cell (DC). DCs pick up antigen within tissues and migrate to local draining lymph nodes for MHC-mediated presentation to antigen-specific T cells and the initiation of adaptive immunity. Furthermore, DCs integrate a variety of secondary cues, such as PRR or cytokine stimulation, to dictate the fate of T cell activation. For example, it is not surprising that mucosal-resident DCs are locally primed for the homeostatic induction of peripheral regulatory T cells (Tregs) via production of TGFβ and retinoic acid, whereas those DCs elicited in the context of infection can skew T cell activation toward inflammatory Th1, Th2, or Th17 subsets, depending on the nature of the pathogen. A similar set of considerations can be applied to monocytes and tissue-resident macrophages. Although less efficient at antigen presentation than DCs, several macrophage-derived cytokines can influence T cell polarization and activation, including IL-1β, IL-23, IL-12, and TNFα. This communication with T and B cells is bidirectional. T cell-derived IFNγ and IL-4 or IL-10 are classically associated with the differentiation of monocytes and macrophages to so-called M1 and M2 phenotypes, respectively. M1 macrophages produce high levels of reactive oxygen species and proinflammatory cytokines and chemokines, whereas M2 macrophages produce high levels of IL-10 and tissue-remodeling factors. However, this remains an oversimplification of the complex macrophage phenotypes in vivo . Similarly, macrophages express high levels of FcγRs, cell surface receptors that bind to the Fc portion of IgG antibodies, and mediated potent cellular responses to opsonized microbes, immune complexes, or deposited IgG.

In recent years, there has been increasing appreciation for the role of certain subsets of granulocytes in the activation of adaptive immunity, particularly with regard to B cell activation and maintenance. Neutrophils have been described to promote antibody production by splenic marginal zone B cells via their production of B cell activating cytokines and costimulatory molecules, such as IL-21 and CD40L, respectively. Furthermore, these cells express FcγRs, with the potential for IgG-mediated feedback. There is also evidence that neutrophils can traffic to lymph nodes (LNs) for presentation of antigen to T cells or licensing DCs for T cell activation by TNFα-mediated maturation. Eosinophils have also been demonstrated to be a major determinant of B cell maintenance within the bone marrow and mucosal tissues via similar mechanisms. Given their residency and recruitment to numerous tissues, it is likely that these cells can influence the induction or progression of alloimmunity.

ILCs are critically dependent on, and influence the activity of, neighboring immune cells, including those of the adaptive immune system. Indeed, seminal work by Sonnenberg and colleagues has demonstrated that ILC3s are capable of MHC class II-mediated antigen presentation and the suppression of antigen-specific T cells within the gut. Similarly, others groups have shown that lung-resident and systemic ILC2s and ILC3s are capable of driving T cell activation in a MHC-II-dependent manner. Furthermore, human splenic ILCs support B cell antibody production through the production of B cell activating molecules, including a proliferation-inducing ligand (APRIL) and B cell activating factor (BAFF), and maintenance of B cell-helper neutrophils.

Stimulation of Adaptive Alloimmunity

The antigen-specific or adaptive immune response to a graft occurs in two main stages. In the afferent arm, donor antigens stimulate recipient lymphocytes, which become activated, proliferate, and differentiate while sending signals for growth and differentiation to a variety of other cell types. In the efferent arm, effector leukocytes migrate into the organ and donor-specific alloantibodies are synthesized, both of which cause tissue damage. To initiate adaptive immunity, the graft must express antigens that are recognized by the recipient as foreign, and these include ABO antigens, HLA, and non-HLA “auto-antigens” that are polymorphic.

ABO Blood Group Antigens

When allocating an organ to a potential recipient the first consideration is to ensure that it is compatible for the ABO blood group antigens. ABO antigens are expressed by most cell types in organ allografts and, were an ABO incompatible transplant to be performed, the presence of naturally occurring anti-A and anti-B antibodies in recipients will likely cause antibody-mediated hyperacute rejection and rapid graft loss. Organs from blood group O donors may be safely given to recipients of any blood groups (“universal donor”) and recipients who are blood group AB may safely receive organs from donors of any blood group (“universal recipient”). In practice recipients of organs from deceased donors receive ABO blood group identical organs to avoid inequity of access to organs, although recipients of kidneys from living donors often receive an ABO compatible but non-ABO identical kidney.

HLA Molecules

Histocompatibility antigens differ between members of the same species and are therefore targets of the immune response in allogeneic transplantation. In all vertebrate species, histocompatibility antigens can be divided into a single, albeit multigenic, MHC and numerous minor histocompatibility (miH) systems. Incompatibility between donor and recipient for either MHC or miH leads to an immune response against the graft, more vigorous for MHC than miH. Indeed rejection of MHC-compatible organ grafts is often delayed, sometimes indefinitely, although in some mouse strain and organ combinations miH differences alone can result in acute rejection similar to that observed across full MHC mismatch. On the other hand, the outcomes of allogeneic stem cell transplantation between HLA-identical siblings can be significantly affected by miH mismatches causing graft-versus-host disease.

Major Histocompatibility Antigens

MHC class I proteins are cell surface glycoproteins composed of two chains—the alpha chain, which is highly polymorphic and encoded by a class I gene, and a nonvariable β ₂ -microglobulin chain (molecular weight approximately 12 kD). MHC class I proteins are expressed on most nucleated cells, albeit at variable levels, and they are generally responsible for activating cytotoxic CD8 T cells. MHC class II proteins are encoded entirely within the MHC and are composed of two membrane-anchored glycoproteins, an alpha and a beta chain. MHC class II molecules present peptides and activate CD4-expressing helper T cells. The tissue distribution of MHC class II proteins is far more restricted than that of class I, being expressed constitutively only by B lymphocytes, DCs, and some endothelial cells (particularly in humans). During an immune or inflammatory response, many other cell types may be induced to express MHC class II proteins.

Both MHC class I and MHC class II molecules have the capacity to present peptides but the origin of these peptides differs between the two. In the case of MHC-I, they are largely acquired from the intracellular environment, whereas MHC-II largely present peptides acquired from the extracellular environment. Nevertheless, so called “cross-presentation” between these pathways may occur, particularly in the context of specialized antigen presentation by DCs.

A combination of MHC and peptide forms a compound epitope that is engaged by the antigen-specific T cell receptor (TCR). The peptide-binding groove is usually occupied by many different peptides, derived from self-proteins (often those from the MHC) which, during infection, are replaced by those derived from pathogens. The TCR repertoire is subject to negative thymic selection so that autoreactive cells are purged and positive thymic selection for TCRs that engage with peptides presented by autologous MHC occurs. When a pathogen invades, MHC proteins become loaded with foreign peptides that are engaged by TCR in a self-restricted immune response.

In humans, the HLA class I molecules are HLA-A, -B, and -C; MHC class II molecules are HLA-DR, -DP, and -DQ. Their role in presenting antigenic peptide to the TCR has led to the evolution of a high level of genetic diversity such that there are thousands of variants of both MHC class I and class II genes in the human population. This is likely to have evolved in response to their role as restriction elements in the response to pathogen-derived peptides. Certain cohorts of animals within species that have limited polymorphism at MHC loci have been devastated by infections that are cleared without difficulty in closely related species with polymorphic MHC. This genetic diversity in the MHC loci is an important driver of alloimmune sensitization stimulated by pregnancy, blood transfusion, and prior transplantation. The immune mechanisms involved in these responses are not fundamentally different from those involved with any other antigen. The cellular immune response to alloantigen is, however, fundamentally different at least in magnitude, because MHC molecules bind a diverse range of endogenous peptides, which are therefore normally presented at the cell surface. Allogeneic MHC generate a correspondingly wide range of compound epitopes distinct from the repertoire generated by syngeneic MHC. These are therefore recognized as foreign and engaged by the TCR in the so-called “direct alloimmune response.” The cellular immune response to MHC alloantigens is consequently unique in its diversity and therefore the number of T cells that can be recruited to an immune response. Clinically, we currently assess and attempt to optimally match transplant donors and recipients according to the number of HLA-A, -B, and -DR mismatches, with a minimum of 0 mismatches (0-0-0) and a maximum of 6 mismatches (2-2-2) considered in the algorithm. In general, a greater emphasis is placed on matching at DR loci because of the capacity of MHC-II mismatches to activate CD4 T cells.

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