David A. Ostrov

Publications (2)20.83 Total impact

• Source

  Available from: Yuri A. Pompeu

  Article: The structural basis of HLA-associated drug hypersensitivity syndromes.

  Yuri A Pompeu, Jon D Stewart, Simon Mallal, Elizabeth Phillips, Bjoern Peters, David A Ostrov
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  ABSTRACT: Recent data suggest alternative mechanisms that promote human leukocyte antigen (HLA)-associated drug syndromes. Hypersensitive responses have been attributed to drug interactions with HLA molecules, peptides presented by HLA molecules and T-cell antigen receptors. Definition of an increasing number of HLA-associated drug syndromes suggests that polymorphism in the antigen-binding cleft residues influence recognition of specific drugs. Recent data demonstrate that small molecule drugs bind within the antigen-binding cleft of HLA in a manner that alters the repertoire of HLA-bound peptide ligands. This drug recognition mechanism permits presentation of self-peptides to which the host has not been tolerized. This altered repertoire mechanism is analogous to massive polyclonal T-cell responses occurring in mismatched HLA organ transplantation in which the drug in effect creates a novel HLA allele. Alteration of the self-peptide repertoire by HLA-binding small molecules may be the mechanistic basis for a diverse set of deleterious T-cell responses since the antigen-binding cleft has structural features that are compatible with binding drug-like small molecules. Small molecule drugs that bind elements of the trimolecular complex (T-cell receptor, peptide, and HLA) may cause short- and long-term adverse effects by a diverse set of mechanisms.
  Immunological Reviews 11/2012; 250(1):158-66. · 11.15 Impact Factor
• Source

  Available from: Yuri A. Pompeu

  Article: Drug hypersensitivity caused by alteration of the MHC-presented self-peptide repertoire.

  David A Ostrov, Barry J Grant, Yuri A Pompeu, John Sidney, Mikkel Harndahl, Scott Southwood, Carla Oseroff, Shun Lu, Jean Jakoncic, Cesar Augusto F de Oliveira, [......], A Michelle English, Amanda Wriston, Andrew Lucas, Elizabeth Phillips, Simon Mallal, Howard M Grey, Alessandro Sette, Donald F Hunt, Soren Buus, Bjoern Peters
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  ABSTRACT: Idiosyncratic adverse drug reactions are unpredictable, dose-independent and potentially life threatening; this makes them a major factor contributing to the cost and uncertainty of drug development. Clinical data suggest that many such reactions involve immune mechanisms, and genetic association studies have identified strong linkages between drug hypersensitivity reactions to several drugs and specific HLA alleles. One of the strongest such genetic associations found has been for the antiviral drug abacavir, which causes severe adverse reactions exclusively in patients expressing the HLA molecular variant B*57:01. Abacavir adverse reactions were recently shown to be driven by drug-specific activation of cytokine-producing, cytotoxic CD8(+) T cells that required HLA-B*57:01 molecules for their function; however, the mechanism by which abacavir induces this pathologic T-cell response remains unclear. Here we show that abacavir can bind within the F pocket of the peptide-binding groove of HLA-B*57:01, thereby altering its specificity. This provides an explanation for HLA-linked idiosyncratic adverse drug reactions, namely that drugs can alter the repertoire of self-peptides presented to T cells, thus causing the equivalent of an alloreactive T-cell response. Indeed, we identified specific self-peptides that are presented only in the presence of abacavir and that were recognized by T cells of hypersensitive patients. The assays that we have established can be applied to test additional compounds with suspected HLA-linked hypersensitivities in vitro. Where successful, these assays could speed up the discovery and mechanistic understanding of HLA-linked hypersensitivities, and guide the development of safer drugs.
  Proceedings of the National Academy of Sciences 05/2012; 109(25):9959-64. · 9.68 Impact Factor