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Abstract
Natural suppressor activity (NSA) is defined by the non-specific, non-MHC-restricted suppression of in vitro immunological assays, and is mediated by cells found at sites of hemopoiesis. The physiological role of NSA is not known. The experiments described in this thesis implicate NSA in resistance to hemopoietic engraftment and suggest a role in the control of autoimmunity in the non-obese diabetic (NOD) mouse.
Using anti-host antibody instead of irradiation as a conditioning regimen, I found that parental marrow cells administered to an untreated F$\sb1$ hybrid host, which apparently failed to engraft, in fact seeded the host marrow where they remained quiescent. The relative resistance to engraftment in adult recipients pretreated with complete Freund's adjuvant (CFA) and in neonatal recipients suggested NSA as a possible inhibitory mechanism because host NSA is increased in both cases. Conversely, we found that administration of facilitating antibody reduced host NSA. These correlations were extended to engraftment kinetics, which we followed using a sensitive isozyme assay permitting us to track individual donor progenitor cells within the host marrow cavity. NSA in the adult marrow tissue was mediated by Thy1-negative, CD4- and CD8-negative, large, nonadherent, radiosensitive cells. The adoptive transfer of Thy1-negative cells displaying NSA decreased engraftment kinetics. These findings were generalized to other transplantation models, where we observed that only cytotoxic drugs and irradiation doses which decreased host NSA induced chimerism. Based on these observations, I have proposed that hemopoietic engraftment may be controlled by host marrow inhibitory functions rather than cytotoxic rejection mechanisms or the availability of "space". In this scheme, a quiescent reservoir of stem cells, whether donor or host, is downregulated by cycling hemopoietic cells which generate NSA.
In another set of experiments, we observed that a single administration of CFA to young NOD mice prevented the development of diabetes. Increased NSA was suggested to play a role since diabetes is T cell-dependent and T cells are suppressed by NSA. Moreover, the low level of NSA in our NOD mice may account for the elevated incidence of diabetes in the colony. These observations suggest an important relationship between hemopoiesis and immunological tolerance.
