T cell reconstitution after transplantation of purified progenitors

Stanford University, Stanford CA

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Abstract

DESCRIPTION (provided by the applicant): The object of the proposed studies is to develop methods to rapidly reconstitute the T cells and T cell immune functions of mice given lethal total body irradiation and allogeneic (MHC-haplotype matched) bone marrow cell transplants. We have recently identified cells (~0.05%) in the adult mouse bone marrow that are committed T cell progenitors (CTP), and are able to rapidly reconstitute only the T cell lineage of lethally irradiated Ly-5 congenic (C57BL/6 background) hosts. The CTP are purified using flow cytometry and immunofluorescent staining for the Thy-1hiCD2-Lin- phenotype, and can protect the hosts from lethal infections with murine cytomegalovirus (MCMV) when combined with hematopoietic stem cell transplants as compared to stem cell transplants alone. Rapid reconstitution of T cells in lethally irradiated athymic, nu/nu, congenic hosts has been achieved as well. The above studies with congenic mice will be applied to haplotype-matched donor-host combinations, a model for haplotype-matched human parent to child or sibling to sibling transplants, to determine whether rapid T cell reconstitution can be achieved in the allogeneic setting. Currently, immunodeficiency in these human hosts is a major problem due to very slow reconstitution of T cells using T-cell-depleted transplants, and a high proportion of hosts die due to opportunistic infections. We will compare T cell reconstitution of allogeneic hosts given stem cell transplants alone or stem cell transplants plus purified CTP. Kinetics of reconstitution of donor chimeric T cells will be monitored by flow cytometry as well as the function of the donor T cells with regard to MCMV infection and help for antibody responses to injected proteins and heterologous red blood cells. The thymus plays an important role in the rapidity of T cell reconstitution in humans, and the role of the host thymus will be studied by comparing T cell reconstitution using euthymic and athymic hosts. The findings from these studies should provide the basis for an effective approach to T cell reconstitution in immunosuppressed hosts.