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Adverse drug reactions (ADRs) are a major obstacle to drug development, and some of these, including hypersensitivity reactions to the HIV reverse transcriptase inhibitor abacavir (ABC), are associated with HLA alleles, particularly HLA-B*57:01. However, not all [HLA-B*57:01.sup.+] patients develop ADRs, suggesting that in addition to the HLA genetic risk, other factors may influence the outcome of the response to the drug. To study HLA-linked ADRs in vivo, we generated HLA-B*57:01-Tg mice and show that, although ABC activated Tg mouse [CD8.sup.+] T cells in vitro in a HLA-B*57:01-dependent manner, the drug was tolerated in vivo. In immunocompetent Tg animals, ABC induced [CD8.sup.+] T cells with an anergy-like phenotype that did not lead to ADRs. In contrast, in vivo depletion of [CD4.sup.+] T cells prior to ABC administration enhanced DC maturation to induce systemic ABC-reactive [CD8.sup.+] T cells with an effector-like and skin-homing phenotype along with [CD8.sup.+] infiltration and inflammation in drug-sensitized skin. B7 costimulatory molecule blockade prevented [CD8.sup.+] T cell activation. These Tg mice provide a model for ABC tolerance and for the generation of HLA-B*57:01-restricted, ABC-reactive [CD8.sup.+] T cells dependent on both HLA genetic risk and immunoregulatory host factors., Introduction Adverse drug reactions (ADRs) have been defined by the World Health Organization (WHO) as noxious and unintended responses to a drug given at a dose established for the prophylaxis, [...]

Inhibitors of calcineurin phosphatase activity (CNIs) such as cyclosporin A (CsA) are widely used to treat tissue transplant rejection and acute graft-versus-host disease (aGVHD), for which inhibition of gene expression dependent on nuclear factor of activated T cells (NFAT) is the mechanistic paradigm. We recently reported that CNIs inhibit TCR-proximal signaling by preventing calcineurin-mediated dephosphorylation of [Lck.sup.S59], an inhibitory modification, raising the possibility of another mechanism by which CNIs suppress immune responses. Here we used T cells from mice that express [Lck.sup.S59A], which cannot accept a phosphate at residue 59, to initiate aGVHD. Although CsA inhibited NFAT-dependent gene upregulation in alloaggressive T cells expressing either [Lck.sup.WT] or [Lck.sup.S59A], it was ineffective in treating disease when the T cells expressed [Lck.sup.S59A]. Two important NFAT-independent T cell functions were found to be CsA-resistant in [Lck.sup.S59A] T cells: upregulation of the cytolytic protein perforin in tissue-infiltrating [CD8.sup.+] T cells and antigen-specific T/DC adhesion and clustering in lymph nodes. These results demonstrate that effective treatment of aGVHD by CsA requires NFAT-independent inhibition of TCR signaling. Given that NFATs are widely expressed and off-target effects are a major limitation in CNI use, it is possible that targeting TCR-associated calcineurin directly may provide effective therapies with less toxicity., Introduction The suppression of immune responses is one of the pillars of therapeutic strategies to treat autoimmunity, immune-mediated inflammatory diseases, and rejection of transplanted tissue (1-3). Activated T cells play [...]

1. Introduction Mammals are susceptible to a wide range of infectious agents, including, but not limited to, viruses, bacteria, and protozoan parasites. While many microbes cause debilitating illnesses, are responsible [...], Natural killer (NK) cells provide an initial host immune response to infection by many viral pathogens. Consequently, the viruses have evolved mechanisms to attenuate the host response, leading to improved viral fitness. One mechanism employed by members of the β-herpesvirus family, which includes the cytomegaloviruses, is to modulate the expression of cell surface ligands recognized by NK cell activation molecules. A novel set of cytomegalovirus (CMV) genes, exemplified by the mouse m145 family, encode molecules that have structural and functional features similar to those of host major histocompatibility-encoded (MHC) class I molecules, some of which are known to contribute to immune evasion. In this review, we explore the function, structure, and evolution of MHC-I-like molecules of the CMVs and speculate on the dynamic development of novel immunoevasive functions based on the MHC-I protein fold.