Susceptibility as opposed to resistance of mouse strains (eg, BALB/c vs C57BL/6) to Leishmania major has been attributed to a defective Th1 and a predominant Th2-response, resulting in increased IL-4 and IgE production, and decreased interferon gamma (IFN␥) production, macrophage activation and elimination of parasites. Here we report dissection of genetic and functional aspects of susceptibility to leishmaniasis using two contrasting inbred strains BALB/cHeA (susceptible) and STS/A (resistant) and a resistant Recombinant Congenic (RC) Strain, CcS-5/Dem, which carries a random set of 12.5% of genes from the strain STS and 87.5% genes from the susceptible strain BALB/c. Linkage analysis of F 2 hybrids between the resistant RC strain CcS-5 and the susceptible strain BALB/c revealed five loci affecting the response to the infection, each apparently associated with a different combination of pathological symptoms and immunological reactions. The correlation between Th2-type immune reactions and the disease in the F 2 mice was either absent, or it was limited to mice with specific genotypes at loci on chromosomes 10 and 17. This suggests that the resistance vs susceptibility is influenced by mechanisms additional to the postulated antagonistic effects of Th1 and Th2 responses, and that the host's genotype affects the development of leishmaniasis in a complex way. Genes and Immunity (2000) 1, 200-206.
Bone marrow-derived mesenchymal stem cells (MSCs) modulate immune response and can produce significant levels of transforming growth factor-b (TGF-b) and interleukin-6 (IL-6). These 2 cytokines represent the key factors that reciprocally regulate the development and polarization of naive T-cells into regulatory T-cell (Treg) population or proinflammatory T helper 17 (Th17) cells. In the present study we demonstrate that MSCs and their products effectively regulate expression of transcription factors Foxp3 and RORgt and control the development of Tregs and Th17 cells in a population of alloantigen-activated mouse spleen cells or purified CD4 + CD25-T-cells. The immunomodulatory effects of MSCs were more pronounced when these cells were stimulated to secrete TGF-b alone or TGF-b together with IL-6. Unstimulated MSCs produce TGF-b, but not IL-6, and the production of TGF-b can be further enhanced by the anti-inflammatory cytokines IL-10 or TGF-b. In the presence of proinflammatory cytokines, MSCs secrete significant levels of IL-6, in addition to a spontaneous production of TGF-b. MSCs producing TGF-b induced preferentially expression of Foxp3 and activation of Tregs, whereas MSC supernatants containing TGF-b together with IL-6 supported RORgt expression and development of Th17 cells. The effects of MSC supernatants were blocked by the inclusion of neutralization monoclonal antibody anti-TGF-b or anti-IL-6 into the culture system. The results showed that MSCs represent important players that reciprocally regulate the development and differentiation of uncommitted naive T-cells into anti-inflammatory Foxp3 + Tregs or proinflammatory RORgt + Th17 cell population and thereby can modulate autoimmune, immunopathological, and transplantation reactions.
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