Donor-reactive T-cell stimulation history and precursor frequency: barriers to tolerance induction.
Blockade of T-cell costimulatory pathways represents a potent and specific method of preventing naïve antidonor T-cell responses after transplantation in mouse, monkey, and man. However, numerous studies have shown that the presence of donor-reactive memory T cells in the recipient poses a sometimes insurmountable barrier to long-term graft survival and tolerance induction. Here, we discuss the ways in which donor-reactive memory T cells may arise from environmental exposure to pathogens. Pathogen-specific memory T cells, by virtue of the inherent degeneracy of T-cell receptor recognition of peptide:major histocompatibility complex ligands, may exhibit cross reactivity with allogeneic peptide:major histocompatibility complexes and thereby mediate graft rejection. From the recent explosion in knowledge of the heterogeneity of memory T-cell resulting from variations in frequency and duration of antigen exposure, cytokine milieu, site of priming, and a host of other factors, it is becoming increasingly well appreciated that different memory T-cell populations may exhibit differential susceptibilities to tolerance induction. Thus, the immune history of a transplant recipient and frequencies of donor-cross-reactive memory T cells within the various compartments may dictate the likelihood of success or failure of tolerance induction.
Emory Transplant Center, Atlanta, GA 30322, USA. mandy.ford@emory.edu
Mandy L
ML
Ford
Allan D
AD
Kirk
Christian P
CP
Larsen
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D006085:Graft Survival / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance; D007156:Immunologic Memory / Q000276:immunology*; D016030:Kidney Transplantation / Q000276:immunology; D008213:Lymphocyte Activation; D013601:T-Lymphocytes / Q000276:immunology*; D023001:Transplantation Tolerance / Q000276:immunology*; D014184:Transplantation, Homologous / Q000276:immunology
D000911:Antibodies, Monoclonal