Drug induced alloreactivity: A new paradigm for allorecognition

Abstract

Aim Abacavir administration is associated with drug induced hypersensitivity reactions in HIV patients expressing the HLA-B∗57:01 allele. However the immunological effects of abacavir administration in an HLA-B57 mismatched transplantation setting has not been studied. We hypothesized that abacavir exposure would induce de-novo HLA-B57 specific allorecognition. Methods Multiple HIV-specific CD8 T cell clones were generated from HIV infected patients negative for the HLA-B57 antigen, using single cell sorting based on HIV peptide/HLA tetrameric complex staining. The generated T cell clones were assayed for alloreactivity against a panel of single HLA expressing cell lines (SALs), in the presence or absence of abacavir. Cytokine assay, CD137 upregulation and cytotoxicity were used as readout. Results Abacavir exposure did induce de-novo HLA-B57 allorecognition by HIV-specific T cells. A Gag RK9/HLA-A3 specific T cell clone, from an HLA-B57 negative HIV patient, did recognize allogeneic HLA-B57 but only in the presence of abacavir. Abacavir did not induce recognition of any other allogeneic HLA molecules. Another clone from the same patient with the same specificity, but with different TCR Vb usage, did not recognize allogeneic HLA-B57 in the presence of abacavir, suggesting TCR Vb specificity of the drug induced allorecognition. Conclusion Results presented here provide the first evidence that administration of a drug could induce specific allorecognition of mismatched HLA molecules in the transplant setting. Furthermore, HIV-specific memory T cells themselves may participate in the abacavir induced alloreactivity. We suggest that HIV-positive recipients of a HLA-B57 mismatched graft should not receive abacavir until further studies are completed.