Mouse model for analysis of non-MHC genes that influence allogeneic response: recombinant congenic strains of OcB/Dem series that carry identical H2 locus

Abstract

Alloreactivity is the strongest known primary immune response. Its clinical manifestations are graft rejection, graft-versus-host disease and graft-versus-leukemia effect. The strongest stimulation by allogeneic cells is due to incompatibility at the major histocompatibility complex (MHC) genes. However, the non-MHC genes also participate in allogeneic response. Here we present a mouse model for study of the role of non-MHC genes in regulation of alloreactivity and show that they besides encoding antigens also regulate the responsiveness. Recombinant congenic strains (RCS) of O20/A (O20)-c-B10.O20/Dem (OcB/Dem) series have been derived from the parental strains O20 and B10.O20, which carry identical MHC haplotypes (H2 pz ) and therefore their differences in alloantigen response depend only on non-MHC genes. We have tested a MLR response by spleen cells of the strains O20, B10.O20, and 16 OcB/Dem strains through stimulation by cells from strains C57BL/10 (H2 b ), BALB/c (H2 d ), CBA (H2 k ), and DBA/1 (H2 q ) alloantigens. Proliferative response of O20, B10.O20 and OcB/Dem strains to these four alloantigens exhibited a similar but not completely identical pattern of reactivity. The responses to different alloantigens were highly correlated: C57BL/10 -BALB/c r = 0.87, C57BL/10 -CBA r = 0.84, C57BL/10 -DBA/1 r = 0.83. Cluster analysis of the responses by O20, B10.O20, and OcB mice identified groups of strains with distinct patterns of response. This data shows that two main types of genes influence MLR: 1. structural genes for major and minor alloantigens and 2. genes regulating T-cell receptor signal transduction or mediating costimulatory signals by antigen-presenting cells.

Genetics of Host Response to Leishmania tropica in Mice – Different Control of Skin Pathology, Chemokine Reaction, and Invasion into Spleen and Liver

“…The observations of progeny having a phenotype, which is beyond the range of the phenotype of its parents, are not rare in traits controlled by multiple genes. It was observed in different tests of immune responses of RC strains in vitro [31] – [35] and in vivo [28] , [36] . Similarly, analysis of gene expression from livers in chromosome substitution strains revealed that only 438 out of 4209 expression QTLs were inside the parental range [37] .…”

Loci controlling lymphocyte production of interferon γ after alloantigen stimulation in vitro and their co-localization with genes controlling lymphocyte infiltration of tumors and tumor susceptibility

“…The BALB/cHeA-c-STS/A (CcS) and O20/A-c-B10.O20/Dem (OcB) series of strains were used previously for analysis of alloantigen response. The strain distribution pattern of magnitude of proliferative response in MLR of individual RC strains to stimulator cells of four different strains was almost identical, indicating that differences in responsiveness, rather than the alloantigenic difference itself, determine the magnitude of the response, and that the responsiveness to different MHC alloantigens is largely controlled by the same genes [ 19 , 20 ]. We have mapped previously two of these responsiveness genes, Alan1 and Alan2 (Alloantigen response 1, 2) located on chromosomes 17 and 4, respectively, that control differences in proliferative response to several alloantigens in CcS and OcB RC strains [ 16 , 17 ].…”