Biomedical subjects

A J Leishman

Publications and source records attributed to A J Leishman.

5 recordsLinked to original sources

PubMed2001

T cell responses modulated through interaction between CD8alphaalpha and the nonclassical MHC class I molecule, TL.

The thymus leukemia antigen (TL) is a nonclassical class I molecule, expressed abundantly on intestinal epithelial cells. We show that, in contrast to other major histocompatibility complex (MHC) class I molecules that bind CD8alphabeta, TL preferentially binds the homotypic form of CD8alpha (CD8alphaalpha). Thus, TL tetramers react specifically to CD8alphaalpha-expressing cells, including most intestinal intraepithelial lymphocytes. Compared with CD8alphabeta, which recognizes the same MHC as the T cell receptor (TCR) and thus acts as a TCR coreceptor, high-affinity binding of CD8alphaalpha to TL modifies responses mediated by TCR recognition of antigen presented by distinct MHC molecules. These findings define a novel mechanism of lymphocyte regulation through CD8alphaalpha and MHC class I.

Amino Acid Motifs↗

PubMed2000

Th1 and Th2 CD4+ T cells provide help for B cell clonal expansion and antibody synthesis in a similar manner in vivo.

The relative ability of Th1 and Th2 T cells to help B cells remains controversial as do the mechanisms by which both T cell subsets provide help in vivo. Whether this help affects the clonal expansion and/or differentiation of B cells has been difficult to assess due to the low frequency of Ag-specific T and B lymphocytes. We have employed a novel technique to directly monitor the clonal expansion of Ag-specific T and B lymphocytes in vivo. OVA-specific TCR transgenic T lymphocytes were polarized toward a Th1 or Th2 phenotype in vitro. These cells were then transferred into syngeneic recipients, along with B cell receptor transgenic hen egg lysozyme-specific B lymphocytes. Our results indicate that Th1 and Th2 cells support B cell responses to a similar extent in vivo and that they achieve this in the same manner by migrating into B cell follicles to promote CD154-dependent B cell clonal expansion and Ab production.

Adoptive Transfer↗

PubMed2000

Induction of oral tolerance in the primed immune system: influence of antigen persistence and adjuvant form.

Oral tolerance is being promoted as a therapy for autoimmune diseases and therefore will need to be functional in a primed immune system. In previous studies, we found that although primed mice could be tolerized by feeding ovalbumin (OVA), the degree of the tolerance and its effects on individual components of the systemic immune response were more limited than that found in naive animals. Here we increased the dose and frequency of antigen feeding in an attempt to extend the effects of oral tolerance in primed mice and to understand why its effects are limited under these conditions. Increasing the amounts of OVA fed, up to a single dose of 400 mg, or using multiple feeds of 5 x 5 or 5 x 25 mg OVA, did not radically alter the extent of tolerance, with DTH responses, antigen-specific proliferation, and IL5 and IFN-gamma production still being tolerized, but antibody responses remaining generally resistant. The deficient tolerance in primed mice could not be overcome by waiting for maximum clonal expansion to wane and was not influenced by persistent release of antigen from a depot adjuvant. We conclude that the resistance of primed mice to oral tolerance may be due to the fact that antigen-experienced T cells may be inherently resistant to induction of tolerance, or that the microenvironment of the primed immune system inhibits the delivery of tolerogenic signals to antigen-specific T cells.

Administration, Oral↗

PubMed1999

Normal induction of oral tolerance in the absence of a functional IL-12-dependent IFN-gamma signaling pathway.

There is considerable evidence that regulatory cytokines play an important role in mediating the systemic tolerance found after oral administration of protein Ags. Although most existing work has focused on cytokines such as IL-4, IL-10, and TGF-beta, recent evidence from TCR transgenic systems suggests that the induction of oral tolerance is accompanied by priming of Ag-specific IFN-gamma production. IFN-gamma has also been implicated as a mediator of T cell tolerance in other models in vivo and in vitro, including that induced by aerosol administration of protein. We show here that feeding tolerogenic doses of OVA primes for IFN-gamma production in the spleen of mice with a normal T cell repertoire. However, depleting IFN-gamma at the time of feeding OVA had no effect on the induction of tolerance. In addition, tolerance was induced normally in both IFN-gamma receptor knockout (IFN-gammaR-/-) and IL-12 p40 knockout (IL-12-/-) mice. This was the case for all components of the systemic immune response and also with a variety of feeding protocols, including those believed to induce distinct regulatory mechanisms. We conclude that IL-12-dependent IFN-gamma-mediated regulation does not play an essential role in oral tolerance.

Administration, Oral↗

PubMed1998

Immunological consequences of intervention in established immune responses by feeding protein antigens.

The usual result of feeding protein antigens to naive animals is the induction of profound immunological unresponsiveness and this is currently being exploited to treat inflammatory disease. Because the most useful therapeutic application of feeding antigen would be to suppress established disease, the aim of this study was to compare the immunological basis of oral tolerance induced by feeding a model antigen to naive and primed animals. We show that feeding 2-200 mg ovalbumin (OVA) to mice 7 days after immunisation with OVA in adjuvant produces dose-dependent suppression of delayed-type hypersensitivity (DTH), T cell proliferation, and both TH1 and TH2 cytokines, although serum IgG levels were unaffected. Feeding OVA before immunisation suppressed all these responses. Although feeding up to 8 days after immunisation could suppress some subsequent responses, tolerance was induced much more effectively when antigen was fed in the first 4 days after immunisation. Tolerance in primed mice was intact in IL-4-/- mice, indicating that it was not caused by selective upregulation of TH2 cells in vivo. We conclude that oral administration of protein antigen can inhibit ongoing responses by all effector T cell subsets, but the exact consequences, and therefore possibly the mechanisms, are different from those induced by tolerising naive mice. These findings may have important implications for designing therapeutic regimes exploiting oral tolerance.

Animals↗