Parameters Involved in the Induction and Abrogation of the Lethal Graft‐versus‐Host Reaction Directed against non‐H‐2 Antigens

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Abstract
The grafting of cells from donors incompatible for non-H-2 antigens alone can lead to GvHR mortality in up to 100% of lethally irradiated adult recipients. GvHR severity correlates with the number of mature immunocompetent cells present in the bone marrow inoculum. Histologic and clinical manifestations of GvHR observed in these mice differ from those seen when GvHR is induced across an H-2 barrier. The number of non-H-2 genes capable of influencing GvHR mortality is probably great, and their effects may vary as a function of sex. The non-H-2 genes influence GvHR mortality mainly via their interactions, the consequences of which are complex and can result in either cumulative or suppressive effects. GvHR mortality is considerably reduced by donor immunization, shortly before grafting, against host-specific non-H-2 antigens; and it is virtually abrogated by an additional immunization of the donors against nonspecific (foreign) H-2 antigens. Three weeks after grafting, these "protected" mice are easily distinguishable from those undergoing lethal GvHR, as assessed by both clinical appearance and histologic examination; in contrast, they are nearly indistinguishable from control mice grafted with syngeneic cells. However, depending upon the conditions used for the immunization, an additional immunization against nonspecific H-2 antigens can lead to acceleration rather than suppression of GvHR mortality; this phenomenon is not seen, under the same experimental conditions, after immunization against specific non-H-2 antigens alone. It is therefore suggested that a "second signal" provided by an additional nonspecific stimulus can potentiate either the establishment of specific suppression or the activation of a secondary ("positive") response. Suppressive effects of the specific and nonspecific immunizations are cumulative, and both treatments activate suppressor cells. The intensity of suppression induced by both specific and nonspecific immunizations is antigen dose-dependent. At equivalent antigen doses the specific immunization is considerably more effective than the nonspecific immunization, and is detectable after injection of as few as 2.5 X 10(5) cells. In both cases, irradiation of the immunizing cells abolishes the suppression induced by the lower cell doses tested, while it merely decreases the intensity of the suppression induced by the higher cell doses tested. The impairment of suppression after irradiation of the immunizing cells is not attributable to a modification of their homing pattern, but to the fact that proliferation of the immunizing cells, which leads to an augmentation of the antigen dose, is abolished by irradiation.(ABSTRACT TRUNCATED AT 400 WORDS)