HLA-Derived Peptides as Novel Immunosuppressives

Department of Cardiothoracic Surgery, Stanford University, Stanford, California, United States
Nephrology Dialysis Transplantation (Impact Factor: 3.58). 06/1997; 12(5):865-8. DOI: 10.1203/00006450-199509000-00001
Source: PubMed


Over the past decade the use of synthetic peptides corresponding to linear sequences of HLA molecules has progressed from a concept to a reality. These peptides are currently being evaluated in clinical trials. In animal models these peptides, given over 1 week with cyclosporin alone, induced long-term immunological tolerance (Figure 3). They may similarly induce tolerance in humans. The next major hurdle for such tolerogenic drugs, however, is to prove efficacy in clinical circumstances. Many of the drugs used to treat transplant patients today (steroids, cyclosporin, azathioprine, mycophenolate mofetil) may actually inhibit the 'active' processes of induction and maintenance of immunological tolerance. Demonstration that new drugs induce tolerance will require efficacy studies in other immune-mediated diseases in which monotherapy is feasible (such as psoriasis), before further advances can be made in the induction of transplant tolerance. In addition, rapid assays of rejection must be developed in order to reverse tolerance induction failures without graft damage or loss. Lastly, it will require heroic physicians, surgeons, and patients to make immunological tolerance a reproducible clinical reality.

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Available from: Alan M Krensky, Apr 23, 2014
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    ABSTRACT: To investigate the role of the indirect pathway of recognition in human allograft rejection, we have mapped the dominant T cell determinant of the HLA-DRβ1*0101 molecule presented by the DRβ1*1101 antigen. A synthetic peptide (pp 22–35) corresponding to the sequence of the dominant peptide determinant was used for testing the frequency ofin vivoactivated T cells in the graft and in the periphery. DRβ1*1101-positive patients carrying a heart allograft mismatched for the HLA-DR1 antigen showed no reactivity to pp 22–35 during quiescence. However, interleukin-2-responsive T cells, which were pp 22–35 specific, were found in the circulation prior to and at the time of acute and chronic rejection. The response ofin vivoandin vitroactivated T cells was inhibited at high concentrations of peptide 22–35. This data suggests that indirect recognition plays an important role in allograft rejection and that it can be abolished by high zone tolerance induction.
    No preview · Article · Apr 1996 · Clinical Immunology and Immunopathology
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    ABSTRACT: In summary, synthetic peptides corresponding to linear sequences of HLA class I molecules can inhibit T-cell responses in vitro and in vivo. These peptides induce immunologic tolerance by binding to hsp-70 family members, causing an increase in intracellular calcium, and down-regulating the nuclear factor of activated T cells, NF-AT. We suggest that heat shock proteins may function as novel immunophilins (Fig 2). Like cyclophilins and FK 506 binding proteins, heat shock proteins are ubiquitous, are involved in protein folding and trafficking, and bind exogenous drugs. Cyclosporine and FK 506 exert immunosuppressive effects by binding immunophilins, which as a result interrupt the phosphatase activity of calcineurin. Although the precise pathways involved in the synthetic HLA peptide effects are not as well worked out, it seems likely that peptide binding to heat shock protein is disrupting normal events in T-cell activation, giving rise to an apparently permanent state of anergy.
    No preview · Article · Sep 1996 · Transplantation Proceedings
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    ABSTRACT: Synthetic peptides corresponding to linear sequences of HLA class I molecules have profound immunomodulatory effects in vitro and in vivo. Recent clinical trials confirm their potential as the therapeutics for transplantation and for a variety of immune-mediated diseases. These peptides also inhibit NK responses in vivo in humans. The importance of the carboxy end of the alpha 1 alpha helix in negative signaling to both T cells and NK cells focuses attention on new targets for immunotherapy.
    No preview · Article · Jan 1997 · Transplantation Proceedings
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