Regulation of Delayed Type Hypersensitivity to Host Histocompatibility Antigens during Graft‐versus‐Host Reactions

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Abstract
During GvH reactions in irradiated mice a variety of specific anti-host immune responses may occur. One of these is the occurrence of DTH to the host histocompatibility antigens, which may account for the inflammatory aspects of GvH. During acute as well as delayed GvH reactions the occurrence of anti-host DTH precedes the clinical symptoms of GvH disease. The anti-host DTH is mediated by long-lived, recirculating Lyt-1 + 2- T cells that need to proliferate in the irradiated recipients in order to display maximum activity. Not all host histocompatibility antigens can elicit anti-host DTH. H-2I and Mls-locus coded alloantigens do, but H-2K/D coded alloantigens and non-H-2 alloantigens other than Mls-locus coded alloantigens do not. This correlates with the ability to elicit proliferative mixed lymphocyte reactions in vitro but is in contrast to the response of nonirradiated mice to sc administered alloantigens. Under the latter conditions, all histocompatibility antigens induce a state of antigen-specific DTH. While the anti-host DTH is mediated by long-lived, recirculating Lyt-1 + 2- T cells, their response can be amplified by short-lived, sessile Lyt-1 + 2 + T cells. The latter T cell subset reacts to the host H-2K/D alloantigens and/or to non-H-2 alloantigens other than Mls-locus coded products. These cells alone cannot mount an anti-host DTH response. The anti-host DTH can be mitigated by Ts cells and non-T suppressor cells. Appropriate Ts cells can be readily induced by iv preimmunization of the donors with 5 X 10(7) irradiated, recipient-type spleen cells. Non-T suppressor cells can be induced by iv injection of bacterial LPS and simultaneous sc injection of 1 X 10(7) recipient type spleen cells. The suppression induced by these protocols shares several characteristics. In both cases the suppression is long-lasting, i.e., lasts at least 50 d, is transferable to syngeneic mice by spleen and lymph node cells, and both suppressive systems affect the induction of anti-host DTH as well as already activated anti-host DTH reactive T cells. Furthermore, while Ts cells and non-T suppressor cells are specific with regard to their antigen recognition, they are both able to suppress the DTH to a completely different set of host alloantigens. This, however, only occurs if the latter are inherited by the irradiated recipients as bystanders to the type of alloantigens that had activated the suppressor cells in the lymphoid cell donors.