Origin and Biology of the Allogeneic Response

Abstract

The recognition by the immune system of nonself determinants on cells, tissues, or organs transplanted between genetically disparate members of the same species can lead to a potent allogeneic response that is responsible for rejection. We review here fundamental concepts that underlie the origins and biology of allorecognition in the mammalian immune system. We examine why and how T cells are alloreactive and discuss emerging evidence of allorecognition by innate immune cells. The nature of T cells (naïve vs. memory) and the alloantigen presentation pathways (direct, indirect, and semidirect) that initiate the allogeneic response are outlined.

HLA-DP in unrelated hematopoietic cell transplantation revisited: challenges and opportunities

“…30 Of note, genetic disparity between unrelated individuals frequently includes the HLA-DRB3/4/5, -DQ, and -DP loci which are targets of direct T-cell alloreactivity, that is, cross-recognition by T cells specific for different self-HLA-restricted peptides regardless of their derivation from novel or recall antigens. 9,10,31 This phenomenon explains why T cells mediating direct alloreactivity are found both in the naive and memory repertoire and have a surprisingly high precursor frequency of at least 1%. 10,24,26,32 HLA-DRB3/4/5, -DQ, and -DP have relatively …”

“…To this end, a protocol for isolation of cytolytic CD4 1 T cells alloreactive to a broad range of HLA-DP specificities from the CD45RA-naive pool, able to eradicate acute myeloid leukemia in a preclinical murine model, has recently been described. 75 T cells with direct alloreactivity can also be found in the memory pool, 9,32,[76][77][78] which might be an even better reservoir given the potential of memory T cells to concomitantly improve immune reconstitution against infective agents. Our extensive understanding of permissive mismatches will help us to carefully select optimal donor-recipient HLA-DPB1 mismatch combinations to minimize the risk of GVHD while maintaining efficient GVL in protocols of adoptive cellular immunotherapy, which hold promise to provide further advances in curing malignant hematological diseases.…”

“…To achieve this ambitious goal, it is crucial to understand the molecular target structures recognized by alloreactive donor T cells mediating these effects. 9,10 These target structures are fundamentally different in allo-HCT from HLA-matched sibling and unrelated donors (UDs), which are often erroneously considered as a single entity ("HLA-matched" HCT). However, in sibling HCT the targets of T-cell alloreactivity are almost exclusively minor histocompatibility antigens (mHAgs), [11][12][13] whereas most HLAmatched UDs additionally present mismatches for the HLA-DP antigens encoded in the major histocompatibility complex (MHC).…”

“…9,[11][12][13] Allorecognition of mHAgs is mediated by conventional self-HLA-restricted, foreign peptide-specific T cells whose repertoire is shaped by positive and negative selection in the thymus. 21,22 Because allogeneic mHAgs are not expressed by thymic antigen-presenting cells (APCs) of self-origin, alloreactive T cells specific for mHAgs occur almost exclusively in the naive T-cell repertoire.…”

Overview of the Indications and Contraindications for Liver Transplantation

“…Although uncontrolled systemic infections, which exclude patient survival under immunosuppression, and AIDS-defining symptoms in HIV patients are absolute contraindications, the possibility of performing a liver transplantation in patients diagnosed with infections such as HBV and HIV and controllable local infections must be assessed for each individual patient (Grossi 2003;Tavio et al 2011;Campsen et al 2013). Further absolute contraindications for liver transplantation are life-limiting medical conditions such as advanced cadiovascular, pulmonary, or neurologic disorders; intrahepatic CCA; hepatic metastases other than neuroendocrine metastases in selected patients; and extrahepatic malignancy (see also Lakkis and Lechler 2013).…”