AUTOLOGOUS GRAFT VS HOST DISEASE

Johns Hopkins University, Baltimore MD

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Abstract

DESCRIPTION: (provided by Applicant) Cyclosporine (CsA), an effective immunosuppressive drug, paradoxically disrupts the mechanisms governing self tolerance during reconstitution of the immune system. Administration of CsA after autologous bone marrow transplantation (ABMT) in rodent models and in man elicits a T-cell dependent autoimmune syndrome with pathology identical to graft-vs-host disease (GVHD) that occurs after BMT. Ongoing studies analyzing the autoreactive lymphocytes in this syndrome termed auto GVHD, provide a unique insight into experimental strategies that augment recognition of tumor associated (TA) antigens. The autoreactive T-cells recognize MHC class II molecules in association with a peptide from the invariant chain, termed CLIP. A specific interaction between the N-terminal region of CLIP and the V-beta segment of the T-cell receptor (TCR) not only strengthens the TCR-MHC class II - CLIP complex, but also apparently overrides the requirements for classical cell surface restricting elements (i.e. CD4, CD8). Preliminary studies reveal that immunization with chimeric peptide constructs of the N-terminal fragment of CLIP and peptides from TA antigens elicit protective antitumor immunity. The central objective of this proposal, to augment specific antitumor immunity after ABMT, is based on the hypothesis that the N-terminal flanking region of CLIP augments recognition of peptides from TA antigens. The development of vaccine strategies in the setting of auto GVHD is particularly attractive since CsA alters the peripheral T-cell repertoire by allowing the emergence of autoreactive cells from the thymus that can recognize "self" TA antigens. The efficacy of peptide/chimeric peptide vaccines to augment antitumor immunity in auto GVHD will be assessed utilizing a rat tumor model that expresses the Her- 2/neu oncogene. In addition, the efficacy of anti-TA antigen reactive lymphocytes activated with the chimeric peptides will be assessed for their ability to augment antitumor immunity in vivo. Clinical trials will be developed based on the results from the animal model.