INCOMPATIBILITY FOR OR PRE‐IMMUNIZATION AGAINST M1s DETERMINANTS DECREASES LETHAL GRAFT‐VERSUS‐HOST REACTION DEVELOPED ACROSS NON ‐ H ‐ 2 AND/OR H‐2 BARRIERS

Abstract

SUMMARY The effect of incompatibility for Mls determinants was studied in lethal graft‐versus‐host reaction (GVHR) in the mouse. GVHR was induced in adult recipients of the following H‐2k strains: (AKR x B10.BR)F1 (MlsB/Mlsb); (C3H x B10.BR)F1 (Mlsc/Mlsb); (CBA/J x B10.BR)F1 (Mlsd/Mlsb) and (CBA/H x B10.BR)F1 (Mlsb). Recipient mice were heavily irradiated and grafted with bone marrow and spleen cells from H‐2 compatible B10.BR (H‐2k, Mlsb) or H‐2 incompatible B10.D2 and B10 donors were normal, while those from B10.BR donors were either normal or pre‐immunized against the recipient strains. In all experiments the survival of recipients with Mlsa/Mlsb and Mlsd/Mlsb phenotypes, and only in one experiment of those with Mlsc/Mlsb phenotype was greater and/or the survival time longer than that of recipients expressing only Mlsb. However, late deaths (> 120 days post grafting) observed after grafting of normal B10.BR cells were more frequent in Mlsd/Mlsb than in Mlsb strains. On the other hand, when B10.BR donor cells were pre‐immunized against H‐2k compatible (AKR x B10.BR)F1 (Mlsa/Mlsb) or (CBA/J x B10.BR)F1 (Mlsd/Mlsb) strains, the survival time of H‐2 incompatible (B10 x B10.BR)F1 (H‐2b/k, Mlsb) recipients was longer than when donor cells were pre‐immunized against (CBA/H x B10.BR)F1 (Mlsb) strain. We conclude that donor incompatibility for Mlsa or Mlsd or donor‐pre‐immunization against Mlsa or Mlsd exerts a protective effect on lethal GVHR developed across non‐H‐2 or H‐2 barriers; the protective effect of Mlsc is less efficient or absent. The Mls‐induced protective effect shows the following properties: (a) efficiency in vivo correlates with the capacity of the corresponding alleles to stimulate an in vitro MLR; (b) is efficient in either primary or secondary response to other minor antigens; (c) is not H‐2 restricted; (d) is nonspecific; (e) disappears late after grafting; (f) with respect to the genetic background, the early protective effect is followed, late after grafting, by an opposite effect which increases the mortality, suggesting that M/s locus determinants are capable of activating several cell populations with different biological functions.

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

“…This conclusion corre-lates with observations suggesting that products of the Mls" locus have a regulatory role in the recognition of other DBA/2 antigens in vitro [20]. As suggested by several experiments [21,221, the suppressive effect of MIS locus products correlates with the capacity of the relevant MIS alleles to stimulate H-2compatible lymphocytes to proliferate. However, whether or not proliferation is in fact necessary for the development of suppression remains to be determined.…”

Oral tolerization ameliorates liver disorders associated with chronic graft versus host disease in mice

“…Oral administration may operate in a similar manner by deleting the reactive cells. 52 In conclusion, using the murine cGVHD model, we have shown that oral tolerization of donor toward recipient splenocyte proteins down-regulated the immune attack by donor effector cells on host target tissue. This led to amelioration of cGVHD of the skin, liver, and small intestines after splenocyte transplantation.…”

Mls and Tolerance

“…The increased survival is mediated by alloimmunization-activated suppressor cells which can decrease the intensity of the immune reaction developed by normal BIO.02 cells both in vivo (GVHR) and in vitro (proliferative response measured in mixed lymphocyte culture -MLC). H-2 GVHR were also suppressed by Mis preimmunization (Halle-Pannenko & Festenstein 1981). Genetic experiments with the congenic strain BALB.D2.Mls' were then designed to test whether the specific antigenic requirement for inducing suppression is indeed the Mis' haplotype.…”