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

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)

Abrogation of the lethal graft‐vs. ‐host reaction developed to non‐H‐2 antigens: involvement of T suppressor cells distinct from veto cells

“…These suppressor cells are, therefore, distinct from veto T cells effective against CTL responses to non-H-2 antigens. These results are in agreement with the fact that, thus far, we have not found a correlation between CTL activity and development or suppression of GVHR [13,14], suggesting that in this genetic combination CTL are not, or are not the only, effector population. It is of course possible that Lyt-2' veto cells might be responsible for alloimmunization induced protection against mortality in H-2 compatible combinations where CTL have been shown to be important in development of GVHR [8], but to our knowledge no direct tests of this hypothesis have been reported.…”

“…administered antigens bypass the presentation of antigen by antigen-presenting cells, which would favor suppression instead of activation [18, 191. Currently, we are studying the possibility that the T suppressor cells described might recognize MIS" antigens in an unrestricted fashion. Studies on the specificity of suppression at the effector phase are in progress, and we already know that donor immunization against DBA/2 antigens (involving Mls") or BALB.D2-MJa (but not BALBlc, Mlsb) antigens, significantly reduces the percent mortality in semi-incompatible H-2d/k F1 recipients, provided that they also express the D B N 2 antigens ( [14], and unpublished results). Thus, the recognition of Mls" antigens seems to be implicated at both the induction and effector phases of the suppression.…”

Significant MLR but not CTL responses against recipient antigens generated in T cells from bone marrow chimeras recovered from acute GVHD

“…1 GVHD is one of the most critical complications accompanying BMT. [2][3][4] To reduce the incidence of GVHD, a number of methods have been established in murine and human systems. [4][5][6][7][8][9][10][11] Elimination of mature T cells from donor BM cells (BMC) is one of the most reliable methods.…”

Comparative Analyses of Thymocyte and Thymic Low‐Density Adherent Cell Functions

“…Even though BMT has developed impressively over the past 40 years, several problems including graft versus host reaction (GVHR) and certain immunodeficiencies still are vexingly difficult (6, 10,16,20,23,28,43).…”

“…Bone marrow transplantation (BMT) is a promising therapy for many diseases of hematopoietic origin including immunodeficiency diseases that are otherwise difficult or impossible to cure (17,21,50). Even though BMT has developed impressively over the past 40 years, several problems including graft versus host reaction (GVHR) and certain immunodeficiencies still are vexingly difficult (6, 10,16,20,23,28,43).…”