The major three themes in this grant application are: 1) the elucidation of lymphocyte homing receptors governing their traffic to organized lymphoid organs and to sites of immune reaction; 2) the definition of maturational lineages of thymic and T lymphocytes; and 3) the definition of maturational lineages of peripveral B and bone marrow pre-B lymphocytes. The major methods of analysis include the isolation of particular subsets of cells at defined stages of maturation both in vivo and in vitro, the analysis of their movement from one stage of maturation to another using well defined markers, and the production of monoclonal antibodies to cells at these defined stages of maturation for phenotypic and functional analyses. The analysis of lymphocyte homing should lead to an understanding of what governs lymphocyte cell-cell interactions necessary for the generation of appropriate (and inappropriate) immune responses resulting from the movement of lymphoid cells into sites occupied by exogenous infectious agents, or autologous determinants in autoimmune disease. The definition of the interaction between lymphocytes and blood vessels within lymphoid organs could also lead to an understanding of various pseudolymphomatous syndromes (for example, angioimmunoblastic lymphadenopathy), or may yet reveal a previously poorly understood congenital or acquired immunodeficiency disease. The analysis of T lymphocyte development is clearly important both for understanding central questions in developmental biology and T cell function, but also should be the key to understanding how T cell deficiency in hypersensitivity diseases arise. The current epidemic of acquired immunodeficiency syndrome is, in fact, the result of elimination of and/or developmental arrest of cells generally defined as helper T cells. Similarly, defining B cell lineage maturation pathways in both antigen independent and antigen dependent sites should lead to an understanding of developmental defects leading to the congenital and acquired agammaglobulinemias, and also the stages at which B cells gain the ability to respond to non-self, but (usually) not to self. Thus these experiments could lead to an understanding of both immunodeficiency and hypersensitivity diseases.
