Immunologic basis of graft rejection and tolerance following transplantation of liver or other solid organs

Abstract

Transplantation of organs between genetically different individuals of the same species causes a T cell-mediated immune response that, if left unchecked, results in rejection and graft destruction. The potency of the alloimmune response is determined by the antigenic disparity that usually exists between donors and recipients and by intragraft expression of proinflammatory cytokines in the early period after transplantation. Studies in animal models have identified many molecules that, when targeted, inhibit T-cell activation. In addition, some of these studies have shown that certain immunologic interventions induce transplantation tolerance, a state in which the allograft is specifically accepted without the need for chronic immunosuppression. Tolerance is an important aspect of liver transplantation, because livers have a unique microenvironment that promotes tolerance rather than immunity. In contrast to the progress achieved in inducing tolerance in animal models, patients who receive transplanted organs still require nonspecific immunosuppressant drugs. The development of calcineurin inhibitors has reduced the acute rejection rate and improved short-term, but not long-term, graft survival. However, long-term use of immunosuppressive drugs leads to nephrotoxicity and metabolic disorders, as well as manifestations of overimmunosuppression such as opportunistic infections and cancers. The status of pharmacologic immunosuppression in the clinic is therefore not ideal. We review recently developed therapeutic strategies to promote tolerance to transplanted livers and other organs and diagnostic tools that might be used to identify patients most likely to accept or reject allografts.

Figure 1

Pathways of alloantigen presentation. Three nonmutually exclusive pathways of allorecognition have been described. (A) In the direct pathway, recipient T cells recognize intact allogeneic MHC molecules on the surface of donor APCs. The direct pathway is responsible for the large proportion of T cells that have reactivity against alloantigens due to cross-reactivity of the T-cell receptor (TCR) with self and foreign MHC molecules. (B) In the indirect pathway, recipient APCs trafficking through the allograft phagocytose allogeneic material shed by donor cells (mostly peptides derived from allogeneic MHC molecules) and present it to recipient T cells on recipient MHC molecules. (C) In the semidirect pathway, recipient APCs acquire intact MHC molecules following direct contact with donor APCs and/or through fusion with donor APC-derived exosomes. These chimeric recipient APCs stimulate recipient T cells through direct and indirect pathways. Modified from Afzali et al.

Figure 2

Lineage commitment of naïve CD4⁺ T cells. Upon activation by cognate antigens and costimulatory signals, recipient naïve CD4⁺ T cells acquire graft-destructive or graft-protective phenotypes, depending on the local cytokine microenvironment in which T-cell activation occurs. In the presence of the proinflammatory cytokines IL-12 or IL-4, CD4⁺ T cells become Th1 or Th2 cells, respectively. The presence of TGF-β and the absence of proinflammatory cytokines turns donor-activated CD4⁺ T cells into tissue-protective Foxp3⁺ Treg cells and prevents T cells from becoming tissue-destructive Th17 or Th1 cells. In contrast, if TGF-β is present with IL-6 or IL-21, the generation of Tregs is blocked and CD4⁺T cells acquire the Th17 phenotype. Each of these subsets expresses specific transcription factors and combinations of cytokines.

Figure 3

Pool size model of the allograft response. The ultimate outcome of graft rejection or tolerance depends on the relative balance between rejection-prone effector T cells and rejection-blocking, immunosuppressive Tregs. In one model, on activation, CD4⁺T cells became terminally differentiated Th1 or Th2 cells; Th1 cells mediate allograft rejection, whereas Th2 cells protect allografts from tissue-destructive Th1 cells. Th2 cells are most prominent in grafts of tolerant hosts. However, allograft rejection still occurs in the absence of Th1 cells, and the recent discovery of 2 additional types of CD4⁺ T cells (Tregs and Th17) that have plasticity has invalidated the Th1 and Th2 model. In a new model, CD4⁺ Tregs, rather than Th2 cells, protect foreign tissues from the destructive effects of cytopathic T cells. Tolerogenic therapeutic strategies differ in their capacity to directly delete effector T cells and/or promote the function and number of Tregs.

Figure 4

Tolerogenic agents modulate the type of T cells that infiltrate the allograft. The fate of the allograft, either rejection or tolerance, depends on the functional balance of alloreactive graft-protecting Tregs to alloreactive graft-destroying T effector cells. In the absence of a favorable change in this balance, Tregs are unable to restrain effector T cells from rejecting the graft. However, in response to tolerogenic agents such as anti-CD154 and rapamycin (RPM), the magnitude of allograft infiltration by effector T cells decreases, whereas the number of natural or induced regulatory T cells (nTregs/iTregs) is preserved or increased. As a consequence, the proportion of allograft-infiltrating Treg to T effector cells is increased in tolerized hosts. The representative intravital microscopy image shows the infiltration of color-coded T cells within the allograft 1 week after transplantation in mice following islet transplantation. Infiltrating nTregs, green; iTregs, yellow; T effectors, red. Modified from Fan et al.

Figure 5

Targets of immunosuppressive drugs used in solid organ transplantation, according to the 3-signal model of T-cell activation. T-cell activation is initiated by signal 1, which is delivered by the interaction between the TCR and the MHC-peptide complex presented by the APC. In transplantation, signal 1 can be delivered through the direct and/or indirect pathways of allorecognition and it defines the specificity of the alloimmune response. Signal 1 alone is not capable of generating productive T-cell responses. However, in combination with signal 2 (also known as the costimulatory signal), signal 1 triggers several intracellular signaling pathways, such as the calcium-calcineurin pathway, mitogen-activated protein (MAP) kinase pathway, and the protein kinase C/nuclear factor κB (NF-κB) pathway; together, these activate transcription factors that mediate cell survival and expression of cytokines. Several cytokines (IL-2, IL-15, IL-4, IL-7, IL-21) induce proliferation (signal 3) through the phosphoinositide 3-kinase (PI3-K) and mammalian target of rapamycin (mTOR) pathways. APCs express different costimulatory molecules; many deliver activation signals that amplify signal 1 and prevent T-cell anergy (eg, CD28-CD80/86 and CD154-CD40 pathways), whereas others inhibit T-cell activation (eg, CTLA4-CD80/86 and PD1-PDL1/PDL2 pathways).

Figure 6

Identification of biomarkers of operational tolerance in clinical transplantation. The search for diagnostic biomarkers of operational tolerance has been conducted mainly in cross-sectional case-control studies, in which peripheral blood samples collected from recipients who became tolerant to transplanted organs after ending immunosuppressive therapy were compared with samples collected from control recipients. In liver transplantation, stable recipients under maintenance immunosuppression with the history of a previous failed attempt at drug withdrawal are used as the control group; in these recipients, the absence of tolerance has been established. Patients who failed to induce tolerance after kidney transplantation and drug withdrawal are not available, so stable recipients who receive maintenance immunosuppression or patients with chronic humoral rejection are used as the control group. In these studies, the confounding effects of pharmacologic immunosuppression are of concern; biomarker discovery trials should be designed as prospective studies in which immune monitoring analyses are performed before immunosuppressive drugs are discontinued. These types of studies have only been attempted with patients undergoing liver transplantation.