T Lymphocyte Responses to Nonpolymorphic HLA-Derived Peptides Are Associated With Chronic Renal Allograft Dysfunction

Background. The routine assessment of cellular alloimmunity to guide therapy is of perennial interest because this limb of the immune system is the main target of current transplant immunosuppression. That this has not as yet been realized in clinical practice reflects the difficulty of developing a standardized assay that accounts for the high degree of polymorphism exhibited by histocompatibility antigens. Methods. We have investigated whether immune responses to peptides derived from nonpolymorphic regions of human leukocyte antigen arise after transplantation, in particular in those with chronic allograft dysfunction. Results. Peripheral blood mononuclear cell gamma-interferon production to peptides derived from the nonpolymorphic alpha 3 domain of class 1 human leukocyte antigen occurred more frequently in long-term renal transplant recipients than healthy controls (51/110 vs. 1/18, 46.3% vs. 5.5%; P <0.001). These responses were associated with chronic allograft dysfunction manifested by a reduced and decreasing estimated glomerular filtration rate (responders vs. nonresponders: 39.5 vs. 48.8 mL/min, P = 0.015 and -4.1 vs. -1.3 mL/min/year, P=0.008). Responses occurred mostly to autologous, "cryptic self-epitopes" and arose from CD4(+)CD25(Hi)CD127(Hi) T lymphocytes, which have been previously implicated in chronic rejection. Conclusion. These findings suggest a strategy for assessing cellular immune responses to transplantation antigens with potential for generalization.