Transplant Lymphocyte Research Articles

P.086: Endoplasmic reticulum stress in recipient spleen follicular B lymphocytes in transplantation may affect the alloimmune response of T lymphoctes.

P.086: Endoplasmic reticulum stress in recipient spleen follicular B lymphocytes in transplantation may affect the alloimmune response of T lymphoctes.

Tissue-Resident Lymphocytes in Solid Organ Transplantation: Innocent Passengers or the Key to Organ Transplant Survival?

Short-term outcomes of solid organ transplantation have improved dramatically over the past several decades; however, long-term survival has remained static over the same period, and chronic rejection remains a major cause of graft failure. The importance of donor, or "passenger," lymphocytes to the induction of tolerance to allografts was recognized in the 1990s, but their precise contribution to graft acceptance or rejection has not been elucidated. Recently, specialized populations of tissue-resident lymphocytes in nonlymphoid organs have been described. These lymphocytes include tissue-resident memory T cells, regulatory T cells, γδ T cells, invariant natural killer T cells, and innate lymphoid cells. These cells reside in commonly transplanted solid organs, including the liver, kidneys, heart, and lung; however, their contribution to graft acceptance or rejection has not been examined in detail. Similarly, it is unclear whether tissue-resident cells derived from the pool of recipient-derived lymphocytes play a specific role in transplantation biology. This review summarizes the evidence for the roles of tissue-resident lymphocytes in transplant immunology, focussing on their features, functions, and relevance for solid organ transplantation, with specific reference to liver, kidney, heart, and lung transplantation.

B lymphocytes in transplantation (abstract)

B lymphocytes are cells of the lymphoid lineage that express antibody as their surface antigen receptor (BCR). The principle purpose of B cell activation by antigen is to induce their differentiation into antibody-producing plasma cells, via a germinal centre reaction ( Figure 1 ). In addition, B cells act as important antigen-presenting cells, activating CD4 T cells and may also produce immunoregulatory cytokines such as interleukin (IL)IL10. B cells influence allograft outcomes in transplantation via antibody production (HLA and non-HLA antibodies) contributing to acute and chronic antibody-mediated rejection (ABMR), may drive T cell mediated rejection (TCMR) via antigen presentation, and influence the development of transplant tolerance via IL10 production [1] . A better understanding of basic B cell biology is required to develop therapeutic strategies that target B cells, allowing improved control of humoral responses in transplantation; Data show that the B cell activation threshold is determined by BCR affinity for antigen and by positive and negative co-signals, including those provided by CD4 T cells, such as co-stimulation via CD40-CD40L interactions and via cytokines such as IL4 and IL21 and those produced by myeloid cells, for example, BAFF [2] . High serum levels of BAFF have been associated with an increased risk of developing de novo donor-specific antibodies and of ABMR in sensitised subjects [3] , [4] . A small proportion of plasma cells arising from the germinal centre become established as long-lived plasma cells in the bone marrow. They reside within a number of limited niches, do not proliferate, but act as long-term antibody factories, producing IgG. Plasma cells have also been described in inflamed tissues in autoimmunity and within allografts [5] . A number of these processes may be amenable to therapeutic targeting, and this will be discussed [6] .

Immune Thrombocytopenic Purpura Due to Passenger Donor Lymphocytes in Liver Transplantation

Introduction: Thrombocytopenia is a frequent complication following solid organ transplant but previous reports suggest that the incidence of immune mediated thrombocytopenic purpura (ITP) following liver transplantation is low (0.7%). Although the mechanisms involved in post transplant thrombocytopenia are complex, the presence of alloantibody derived from passenger donor lymphocytes should be considered when severe thrombocytopenia is identified.Case presentation: Our case is a 58-year-old gentleman who underwent liver transplantation for end stage cirrhosis and hepatocellular carcinoma. His baseline pre-transplant platelet count was low at 83 ×109/L, but he postoperatively worsened to a platelet count of 5×109/L with bleeding sequelae. The liver donor was a 71-year-old previously healthy man who presented with severe thrombocytopenia (platelet count of 3 ×109/L) and hemorrhagic stroke, but no evidence of hematological pathology on bone marrow examination. As the donor history of presumptive ITP was known to the service, antiplatelet antibody assays on both the donor and recipient were performed using the ELISA based GTI-PAK12 kit (GTI Diagnostics, Waukesha, WI). Although there were no detectable antiplatelet antibodies in the organ recipient's pre-transplant specimens, the immediate post-transplant specimen demonstrated reactivity in all three GPIIb/IIIa wells, corresponding to a stronger but identical reaction pattern in the organ donor. This suggested that the reactivity and subsequent worsening of the thrombocytopenia were secondary to antibodies produced by passenger donor lymphocytes in the transplanted liver. The transplant recipient was treated with corticosteroids, intravenous immune globulin and platelet transfusion with a return to his baseline platelet count and cessation of bleeding symptomatology five days later. Repeat platelet antibody testing in the organ recipient five weeks post-transplant revealed no detectable antiplatelet antibody reactivity, indicating lack of engraftment of the passenger donor lymphocytes.Conclusion: Passenger donor lymphocytes producing antiplatelet antibodies may be a contributing factor in post-transplant thrombocytopenia. Close monitoring and high clinical suspicion should be present when there is a history of immune/idiopathic thrombocytopenia in the organ donor.

Immunobiology of natural killer lymphocytes in transplantation.

Natural killer (NK) lymphocytes are powerful effector cells of the peripheral immune system. NK cell functions are controlled by the expression of a variety of cell surface receptors with either inhibitory or activating roles. The genetic and functional diversity of this repertoire of receptors and the role of human leukocyte antigen class I histocompatibility molecules as a major group of NK receptor ligands endows NK cells with an innate alloreactive capacity. Early studies of experimental bone marrow transplantation revealed an important role for NK cells in the rejection of allogeneic grafts and contributed significantly to our understanding of NK cell behavior. Both animal models and in vitro studies have since implicated NK cells as contributors to the pathology of clinical transplantation. However, recent clinical studies have demonstrated the potential benefits of exploiting NK cell alloreactivity in mismatched hematopoietic stem cell transplantation for particular types of acute leukemia. Future investigations of NK cell alloreactive functions will undoubtedly reveal additional roles and potential therapeutic applications of this fundamental cell type in clinical transplantation.