Host age and H-2 tolerance in chimeric mice: Mixed lymphocyte reactivity,cell-mediated lympholysis and responses to hapten-modified self

In order to further our understanding of the reasons for the increased susceptibility of aged animals to autoimmunity, neoplasms and infectious diseases, experiments were performed to determine the ability of an aged environment to induce and support tolerance to major histocompatibility complex (MHC) determinants as well as to support the development of a specific immune response to modified self-determinants. The degree and mechanisms of tolerance to host and donor histocompatibility antigens were studied in bone marrow chimeras of the type (C57B1/6 × CBA)F₁ → (C57B1/6 × DBA/2)F₁ (BCF₁ and BDF₁, respectively). BCF₁ bone marrow donors were 6 weeks old and BDF₁ hosts were 18 months old at the time of chimerization. Four to ten months later, chimeras were found to be fully tolerant to all three parental haplotypes and competent to respond to fourth-party strains as assessed in both mixed lymphocyte reactions and cell-mediated lympholysis. Tolerance to parental haplotypes could not be attributed to active suppression of reactivity.The aged host environment proved incapable of supporting the development of anti-modified self-reactivity as attested by the fact that neither the senescent BDF₁ mice nor the BCF₁ → BDF₁ chimeras established in aged hosts could respond to trinitrophenol-modified autologous parental cells. In contrast, young BDF₁ mice and BCF₁ → BDF₁ chimeras established in young adult hosts were competent to respond to trinitrophenol-modified autologous and parental cells in an MHC restricted fashion. The significance of these results to the susceptibility of aged animals to intracellular parasitic infections and neoplasia is discussed.