Neonatal bone marrow-(B) and thymus-(T) derived lymphocytes exhibit considerable self-reactivity. Autoimmunity is averted however, the mechanisms remaining to be defined. Characterization of lymphocyte interactions that result in regulation of autoreactivity is the goal of the application. CD5 B-cells, distinguished by predominance at birth, presence in the thymus, and expression of anti- self specificity, may represent an important self-antigen-presenting cell in the establishment of T-cell tolerance. Studies outlined in this application are designed to do the following: 1. Establish in vivo and in vitro models for self-reactivity that permit analyses of the generation of self-tolerance in neonatal T-cells. This will be done in vitro by assessing the proliferative response of syngeneic, neonatal versus adult, T-cells co-cultured with adult B-cells (autologous mixed lymphocyte reaction, AMLR) and, in vivo by testing the ability of these T-cells to induce Ig production in SCID recipients. The kinetics of the functional inactivation of self-reactive T-cells for BALB/c and B-cell defective X- chromosome-linked immune-defective (XID; BALB.xid) mice will be compared as differences between these strains will indicate a role for B-cells in the induction of T-cell tolerance. 2. Determine the role of B-cell maturation-defective XID mice as adoptive recipients of purified B-cell subpopulation; tolerance will be assessed using the AMLR. 3. Determine if levels of T-cell-regulatory lymphokines are increased as a consequence of neonatal T-cell and B-cell interaction. Sensitive RNase protection assays that allow quantitation of IL-1 alpha, IL-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-10, gamma-IFN, TNF-alpha, and TNF-beta mRNAs will be employed to assess the types of lymphokines produced and their kinetics when neonatal T-cells and specific B-cells subpopulations are co-cultured. The long-term goal of this project is to characterize the neonatal immune system, identifying the lymphocyte interactions that lead to the induction of tolerance to self-antigens. The broad purpose of these studies is to generate novel strategies for preventing autoimmunity by cellular- intervention during the ontogeny of immunity.
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