A new type of genetic regulation of allogeneic response. A novel locus on mouse chromosome 4, Alan2 controls MLC reactivity to three different alloantigens: C57BL/10, BALB/c and CBA

Abstract

The intensity of the mixed lymphocyte response (MLR) depends on the genetic disparity between the donors of responding and stimulating cells. Differences in the major histocompatibility complex (MHC) and Mls1 antigens induce the strongest responses. However, even with comparable incompatibilities in MHC and Mls antigens, some strains of genetically defined mice respond remarkably better than other strains. Apparently other, so far undefined, genetic factors contribute to the magnitude of the MLR. The strain OcB-9 (H2 pz ) has 87.5% genes from the strain O20/A (O20) and 12.5% genes from strain B10.O20 (both H2 pz ). In spite of the overal similarity of their genomes, OcB-9 mice differed from O20 mice in response to three different alloantigens C57BL/10 (H2 b ), BALB/c (H2 d ) and CBA (H2 k ). As both O20 and OcB-9 strains carry identical haplotype H2 pz , their differences in alloantigen response depend only on non-MHC genes. We analyzed the genetic basis of these strain differences using (OcB-9 × O20)F 2 hybrids, and we mapped a novel locus Alan2 (Alloantigen response 2) on chromosome 4 near D4Mit72 that influences the response to all alloantigens tested. This linkage was significant for C57BL/10 and for BALB/c alloantigens (corrected P values 0.0475 and 0.0158, respectively) and highly suggestive for CBA (corrected P = 0.0661). The response to DBA/1 (H2 q ) alloantigens exhibited a similar pattern but the linkage was not significant. As MLR reflects the recognition phase of transplantation reaction, identification of human counterparts of the Alan genes and a better understanding of the regulation of alloresponsiveness might lead to a better prediction of patients' reactions to allografts and to a more individualized measures to prevent rejection. Genes and Immunity (2000) 1, 483-487.

Genetic Control of Resistance to Trypanosoma brucei brucei Infection in Mice

“…Some F 2 hybrids derived in cross between trypanotolerant African N'Dama ( Bos taurus ) and trypanosusceptible Kenya Boran ( Bos indicus ) cattle differed from both parents and contained less T. congolense parasites than any of them [37]. Similarly, mouse RC strain OcB-9 differs from both parental strains O20 and B10.O20 in response to alloantigens [38], several RC strains exhibit in some parameters higher susceptibility to Leishmania major than both parental strains BALB/c and STS [39], and analysis of gene expression from livers in chromosome substitution strains (background strain C57BL/6, donor strain A/J) revealed that only 438 out of 4209 expression QTLs were inside the parental range [40]. These observations are due to multiple gene-gene interactions of QTLs, which in new combinations of these genes in RC strains, F 2 hybrids or in chromosomal substitution strains can lead to appearance of new phenotypes that exceed their range in parental strains.…”

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

“…Our data indicates, that the observed differences are controlled by several non-linked loci. We have identified one of them as Alloantigen response 2 (Alan2 ) localized near the marker D4Mit72, which controls the response of OcB-9 to C57BL/10, BALB/c, CBA and perhaps also DBA/1 alloantigens [16]. Comparing the previously described genotypes of the OcB strains at this genetic region [45] revealed that B10.O20 derived segment in the region that contains the Alan2 locus is also present in the high responding strain OcB-16.…”

“…The first type includes the structural differences in major and minor antigens and their incompatibility between the stimulating cells and the responder. The second type is most likely based on polymorphism in gene(s) which code factor(s) participating in the T-cell receptor signal transduction or mediating costimulatory signals by antigen-presenting cells [16].…”

“…Some non-MHC loci that modify alloresponse were shown to be minor antigens coded in the mouse by Mtv [13]. Several groups have reported that recognition of a host vSAG (viral superantigens) (Mls1a and Mls2a) by donor T cells may determine the manifestations of GVHD in several parental/F1 strain combinations [14,15], others indicate roles of non-MHC non-Mls genes in MLR [16,17] and in GVHD [18][19][20][21].…”

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

“…Earlier studies found that some strong MLC-stimulations ( Mls ) antigens are coded by mouse Mtv (mammary tumor virus) [ 13 ]; later studies revealed a broad spectrum of additional minor human antigens [ 14 ]. Intensity of MLC-response to alloantigens is determined by two major factors—the genetic disparity between the responding and stimulating cells and the genetically defined intrinsic capacity of the responding cells to react to the stimulus [ 15 – 17 ].…”