This study establishes the important synergistic role of drug concentration and HLA-B*58:01 allele in the allopurinol or oxypurinol-specific T cell responses. Despite the prevailing dogma that Type B adverse drug reactions are dose independent, allopurinol hypersensitivity is primarily driven by oxypurinol-specific T cell response in a dose-dependent manner, particular in the presence of HLA-B*58:01 allele.
It has been well established that T cells can recognize small mol. wt compounds such as drugs. Results from previous studies revealing a high heterogeneity and cross-reactivity of drug-specific T cell clones (TCC) in individual patients prompted us to analyze the degeneracy of drug-reactive TCR in detail. Hence, we analyzed the MHC restriction pattern of a panel of 100 drug-specific TCC isolated from different drug-allergic donors. We found that 28 of the tested clones showed an MHC allele-unrestricted drug recognition. Most of these clones were at the same time highly drug specific, i.e. they could only be stimulated by the original drug and not by any drug derivatives. In contrast, TCC with the ability to interact with different drug derivatives displayed a clearly MHC allele-restricted drug recognition. Therefore, we concluded that the TCR of these clones is mainly interacting with side chains of the appropriate drug molecules and hence able to tolerate alterations in the MHC molecule. Moreover, we tested all clones for additional alloreactivity and found that 27 clones could be stimulated by a self-MHC--peptide--drug complex as well as by a non-self-MHC--peptide complex. This cross-reactivity with allogeneic MHC molecules was substantially higher in drug-specific TCC compared to tetanus toxoid-specific clones from the same donors. This suggests that from the point of view of drug-specific TCR, non-self-MHC--peptide complexes have a higher incidence to mimic the 'original' self-MHC--peptide-drug complex and this may occur for TCR recognizing self-MHC--pathogen-derived peptide complexes. Finally, the biological functions of bispecific TCC were not influenced by the nature of the stimulating ligand. Both drug as well as allogeneic stimulation led to similar reaction patterns in the analyzed TCC.
CD4+ T-helper cells appear to be essential in sustaining immune responses in chronic viral infections, as the maintenance of CD8+ cytotoxic T-lymphocyte responses and the control of viremia were demonstrated to depend on CD4+ T cell help. In order to investigate the function of HIV-specific CD4+ T cells in chronic HIV-1-infection, 49 chronically HIV-infected patients were analyzed before and 3 and 6 months after initiation of antiviral treatment. Ten patients showed a substantial, although weak, proliferative response to HIV-1-p55gag protein for which no improvement was observed upon initiation of HAART. From one individual, HIV-1-p55gag-specific CD4-positive T-cell clones were generated that were heterogeneous in their TCR Vbeta gene usage and HLA-DRB1*13 and DRB1*03 restricted, respectively. In addition, some CD4+ TCC produced substantial amounts of IFN-gamma and MIP-1alpha/beta were perforin-positive, and showed cytotoxic activity. These diverse functional features of HIV-specific CD4+ T cells suggest that they may exert direct antiviral activity.
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