This proposal describes experiments to investigate the specificity for virus and HLA of human lymphocytes which have been cultured with Herpes viruses in assays of proliferation and cytotoxicity. The lymphocytes and target cells will be derived from parents and their children, respectively, so that they share an HLA haplotype. These studies should allow us to determine whether virus specific T cell blasts might eventually be prepared in tissue culture and subsequently used to treat severe infections in related individuals. This information is needed because infection is now the commonest cause of death amongst children with good-prognosis acute lymphoblastic leukemia. Major pathogens are varicella zoster virus (VZV), Herpes simplex virus (HSV) and cytomegalovirus (CMV). Antibody provides only partial protection from these viruses and although VZV and HSV respond acutely to acyclovir there are no treatments for CMV or for the prevention of recurrence of VZV or HSV in immunosuppressed patients. New treatment modalities are therefore needed. Virus specific T cells kill virus infected target cells provided that they have HLA A,B or C antigens in common and parents share one set of these antigens with each child. Unselected parental lymphocytes or unrelated whole blood transfusions are sometimes used to treat severe virus infections but the value of this approach is not established and it carries a small risk of causing graft-versus-host (gvh) disease. Existing information indicates that virus specific T cell blasts separated from antigen stimulated cultures are depleted for alloreactivity so they would be less likely to cause gvh disease in an immunosuppressed recipient. If the source of the blasts were parental they would be expected to be able to recognize virus antigens in the child because of the shared HLA haplotype. However, before the clinical use of virus stimulated blasts were considered, critical questions concerning their freedom from alloreactivity, lack of virus infection and lack of non-specific suppressor activity would have to be answered. Our proposed approach to these questions makes use of in vitro cultures of human cells and an in vivo mouse model. We shall also judge the appropriateness of our treatment goal by further defining the nature of the immunodeficiency in treated leukemics in remission.
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