SOJ Immunology

Number 7, 2015

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The Special Issue on Immunobiology of Transplantation

Authors: Mepur H. Ravindranath

Abstract

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The era of organ transplantation began when Emerich Ullmann, an Austro-Hungarian professor of surgery, performed the first intestinal transplant (1889), for which he was regarded as “the father of intestinal transplantation” [1]. On March 7, 1902, he performed the first kidney transplant on a human, anastomosing a pig kidney into the cubital region of a woman with end-stage renal disease; the transplant failed. His 1914 monograph on the state of the art of transplantation, “Tissue and Organ Transplantation”, summarized what then seemed the insurmountable immunological barriers to transplantation [1]. It would take almost 50 years before effective means of immunosuppression were developed, becoming available in the 1950s [2]. However, in 1902-Ullmann had successfully performed an autotransplant of a dog’s kidney to its throat. In 1908, French surgeon Alexis Carrel performed the same auto transplant of a dog’s kidney, showing that “such a transplant doesn’t interfere with the kidney function,” which meant that, at least as a matter of surgery, organ transplantation was a reality. This earned Carrel the Nobel Prize in 1912. Subsequently, several other Nobel laureates laid the foundation for the immunobiology of transplantation. They included Sir Peter B. Medawar, Sir F. Macfarlane Burnet, Baruj Benacerraf, Jean D.G.J. Dausset, George D. Snell, Joseph E. Murray and E. Donnall Thomas.

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Model of Chronic Allograft Injury in Alloantibody Positive Renal Transplant Patients

Authors: Matthew J. Everly

Abstract

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Despite significant efforts, long-term outcomes in transplantation have not substantially improved over the past few decades. Nonetheless, innovations in immunosuppression have led to the control or a better understanding of T-cell mediated responses. By improving control of the T-cell immune response with immunosuppression, acute cellular rejections have substantially decreased while long-term outcomes remain the same. Transplant researchers have now shifted their focus to the humoral arm of the immune system. It is thought that a significant proportion of transplants experience failure as a result of human leukocyte antigen antibody-mediated injury. Recent studies of the natural history, mechanisms, and pathologic signatures for antibody-mediated injury have led to advancements. This review outlines these advancements and the current understanding of the model of chronic alloantibodymediated injury and describes a path to improve outcomes as they relate to alloantibodies in transplantation.

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Tolerogenic Mechanisms in Liver Transplantation

Authors: Elaine Y. Cheng, Paul I. Terasaki

Abstract

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The liver has unique tolerogenic properties which have been recognized since the beginning of liver transplantation. The liver allograft not only demonstrates a lower incidence of rejection compared with other solid organs, but it also has the ability to protect other organs from the same donor against rejection and graft loss. Up to 20% of liver transplant recipients have been successfully weaned from immunosuppressive therapy while maintaining stable allograft function. Furthermore, the liver has the ability to reverse ongoing rejection of other transplanted organs and counters the deleterious effects of preformed lymphocytotoxic antibodies. Various mechanisms have been proposed to explain the immunomodulatory properties of the liver. These include: (1) the transfer of donorderived hematopoietic cells, called passenger leukocytes, with the liver graft and the creation of donor microchimerism; (2) the role of hepatocytes and non-parenchymal liver cells as tolerogenic antigen presenting cells; (3) the high-dose antigen effect leading to dilution of cytokines and clones of alloreactive T cells; and (4) the introduction of soluble and cell-bound major histocompatibility complex class I molecules by the liver graft. This article will examine the evidence underlying each of these hypotheses and assess their relative significance in the induction and maintenance of donor-specific hyporesponsiveness. An enhanced understanding of the immune processes responsible for transplantation tolerance may lead to the identification of biomarkers for the prediction of graft outcomes. More importantly, this knowledge may facilitate the development of therapeutic strategies to promote indefinite allograft acceptance, while eliminating or minimizing the need for immunosuppressive drugs.

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Immunobiology of HLA Class-Ib Molecules in Transplantation

Authors: Vadim Jucaud, Mepur H. Ravindranath, Paul I. Terasaki

Abstract

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The objective of this review is to elucidate the role of HLA-Ib molecules in transplantation after elucidating their immunobiological potential. Structurally, the non-classical HLA-Ib molecules (HLA-E, HLA-F and HLA-G) are less polymorphic than HLA-Ia molecules. In transplantation, HLA-Ib molecules are emerging as immune regulators, functioning as ligands for immunomodulatory cell surface receptors expressed by the subsets of NK and CD8+ T cells-the major players in allograft rejection. HLA-E is the most pleiotropic molecule in an allograft setting; it can interact with both inhibitory (CD94/NKG2A) and activating (CD94/NKG2C) receptors expressed by NK and CD8+ T cells. This interaction is dependent on the nature and source of peptides presented by HLA-E. When HLA-Ia-derived peptides are presented, HLA-E interacts with CD94/NKG2A, inhibiting the cytotoxic cell functions that promote graft survival. When the HLA-G leader sequence is presented, it interacts mainly with CD94/NKG2C to activate the cytotoxic cells, leading to graft rejection. In addition, HLA-E can present viral and bacterial peptides that can bind to both CD94/NKG2 receptors, and also can interact with the other receptors of CD8+ cells, enhancing the risk of allograft rejection. HLA-G and HLA-F can promote graft acceptance by binding to another family of receptors: the Ig-like transcripts (ILT2/ ILT4) expressed by NK cells. Consequently, higher levels of HLA-G on the cell surface and in circulation promote graft acceptance, survival, and immunosuppression-free status for graft recipients. In contradistinction, overexpression of HLA-Ib results in higher risk of developing Graft-versus-Host Disease (GvHD) in cell transplantation. Soluble HLA-Ib (sHLA-Ib) molecules are augmented in circulation during injury, inflammation and transplantation. The sHLA-Ib can be free or associated with β2-microglobulin. In addition, sHLA-Ib molecules occur in a variety of conformations (isoform); as a result, HLA-Ib exposes epitopes to different immune components, contributing to antibody production. These antibodies can be monospecific or polyreactive. Binding of the monospecific antibodies can block the interaction of HLA-Ib with inhibitory receptors on cytotoxic cells, affecting graft survival. Polyreactive antibodies that bind to both cryptic and non-cryptic domains can affect routine HLAIa antibody screening and organ allocation. The antibodies binding to a cryptic domain are capable of suppressing blastogenesis and proliferation of CD4+ T cells as well as secretion of HLA antibodies by B cells; both could prolong graft survival.

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Immunobiology of Allograft Human Leukocyte Antigens in the New Microenvironment

Authors: Mepur H. Ravindranath, Vadim Jucaud, Paul I. Terasaki

Abstract

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The antibodies formed by allograft recipients against donors’ mismatched allo-human leukocyte antigens (allo-HLA) correlate with graft rejection. This review’s aim is to elucidate the immunological events associated with allografts’ mismatched HLA from transplantation to acute/chronic rejection. Such clarification may permit more precisely relevant therapeutic strategies that can facilitate better graft survival. The trigger event in the allograft microenvironment is an inflammatory response, promoting overexpression of allo-HLA as dimers or monomers. Overexpression of membrane- bound HLA is accompanied by matrix membrane proteases that dissociate and release monomeric HLA from the cell surface, forming soluble HLA (sHLA), and the recipient’s immune components interacting with both membrane-bound and sHLA. Immune recognition of allo-HLA may vary depending on whether the allo-HLA is dimeric or monomeric. An important player in immune rejection of the allograft appears to be sHLA. Monomeric sHLA that are free of b2-microglobulin (b2m) bind to receptors of allogenic cytotoxic T cells (NKT and CD8+ T cells) to prevent cytolytic destruction of the allograft, and they expose epitopes that b2m made cryptic. The antibodies formed against donor-specific allo-sHLA during acute/chronic rejection cause arteriosclerosis and affect the glomerular filtration rate, leading to allograft rejection. Anti-HLA antibodies can be diverse, some recognizing specific epitopes on the mismatched allo-HLA, others recognizing the cryptic but common shared epitopes b2m previously masked. When monoclonal antibodies to sHLA were generated, it was shown that the functions of monospecific antibodies differ from those of polyreactive antibodies, which recognize epitopes shared with all HLA-I alleles and suppress T-cell proliferation while monospecific antibodies can induce proliferation of CD8+ T cells. Knowing the physicochemical structure of HLA-I/-II is essential for the elucidation of HLA functions. Although the functional potentials of N-linked carbohydrates located at the junction of the antigen-presenting groove remain unexplored, anti-HLA antibodies are monitored by coating recombinant HLA (rHLA) on solid matrices. The coated rHLA are not glycosylated nor is the ratio of monomeric and dimeric rHLA constant for all alleles. This review emphasizes that until these issues are resolved, we cannot comprehend why several allograft recipients do not show any signs of pathogenicity or rejection episodes post-transplantation in spite of the presence of donor specific allo-HLA Abs.