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Abstract
The studies in this thesis were designed to determine the mechanisms of immunosuppression induced in rodents by total lymphoid irradiation (TLI). TLI was administered in 17 daily doses of 200 rads to a total dose of 3,400 rads, and has been previously shown to result in a long-term reduction in the number and function of T lymphocytes in irradiated animals. The experimental strategy of these studies involved investigation of possible changes in the levels of lymphocyte sub-populations in the spleen and lymph nodes of irradiated animals, and investigation into the generation of suppressor cells by TLI in these mice. Attempts were then made to determine what role such documented alterations might play in the immune potential of TLI-treated animals.
The presence of lymphocyte sub-populations bearing various surface markers was investigated using a battery of alloantisera specific for various markers in a complement-mediated cytotoxicity assay. Although the levels of most surface marker-positive cells in animals one month after TLI were similar to those of normal controls, the percentage of TL('+) cells in both spleen and lymph nodes was up to 20-fold higher than that of normals. The TL antigen is not found on cells in the peripheral tissues of normal animals, but is found on thymocytes. Using a cell transfer system, spleen cells from TLI-treated mice were shown to be capable of suppressing an adoptive secondary anti-DNP response, and elimination of the TL('+) cells also eliminated this suppression. The results indicate that a sub-population of cells ordinarily found only within the thymus is present in large numbers in peripheral tissues following TLI, and suggest that such cells function in the suppression of humoral responses in TLI-treated animals.
In addition, the presence of cells capable of non-specific suppression of the mixed lymphocyte reaction (MLR) was documented in TLI-treated mice. The suppressor cell was characterized as a Thy-1('+), TL('-) cell present in the spleen, but not the lymph nodes, of irradiated animals. The MLR suppressor cells were also shown to be capable of suppression of graft-versus-host disease (GVHD) in vivo when transferred into lethally irradiated recipients reconstituted with allogeneic bone marrow (BM) cells. Taken together with the above results, these studies suggest that two sub-populations of suppressor cells, distinguishable on the basis of cell surface phenotype, are present in TLI-treated animals and function to suppress different types of immune responses.
Experiments using cells from long-term allogeneic chimeras prepared with TLI indicated that MLR suppressor cells were not present in these animals. However, both chimeric mice and mice given TLI alone did possess cells capable of in vitro suppression of the generation of cytotoxic T lymphocytes. Suppression was specific for donor and host antigens in the chimeras, but was non-specific in mice given TLI alone. These studies suggest that non-specific suppressor cells of MLR and GVHD function in the induction of tolerance to transplantation antigens by suppressing the generation of both donor and host cytotoxic T cells, thereby blocking acute GVHD and preventing bone marrow rejection in the period immediately following transplantation. The activity of such non-specific suppressor cells leads to the generation by donor and host of separate populations of cells which in turn specifically block the generation of host and donor cytotoxic T cells and thus maintain long-term mutual host and donor tolerance.
