Genetics of graft-versus-host disease, I. A locus on chromosome 1 influences development of acute graft-versus-host disease in a major histocompatibility complex mismatched murine model

Abstract

Graft-versus-host disease (GVHD) is the major complication occurring after bone marrow transplantation. The severity of GVHD varies widely, with this variation generally being attributed to variation in the degree of disparity between host and donor for minor histocompatibility antigens. However, it is also possible that other forms of polymorphism, such as polymorphisms in immune effector molecules, might play a significant role in determining GVHD severity. In order to investigate this hypothesis, we are studying the genetic factors that influence GVHD development in a murine model. We here report the first results of this analysis, which demonstrate that a locus on Chromosome 1 of the mouse, and possibly also a locus on Chromosome 4, exert considerable influence over the development of one aspect of acute GVHD - splenomegaly - in a parent-->F1 murine model. These results demonstrate that non-MHC genes can exert quite significant effects on the development of GVHD-associated pathology and that gene mapping can be used as a tool to identify these loci. Further analysis of such loci will allow identification of the mechanism whereby they influence GVHD and may lead in the future to improved selection of donors for human bone marrow transplantation.

Figure 1

Spleen weight of B10D2F₁ recipients 14 days after transfer of 5–6×10⁷ lymphoid cells from B10.D2, DBA/2 or B10D2F₁ donors. Probability values were calculated by Student’s t-test comparison of the indicated groups.

Figure 2

Spleen weight of B10D2F₁ recipients 14 days after transfer of 5–6×10⁷ lymphoid cells from (B10.D2×DBA/2)×B10.D2 (B10BX) donors or (B10.D2×DBA/2)×DBA/2 (D2BX) donors. Probability values were calculated by Mann–Whitney U-test comparison of the indicated groups.

Figure 3

Spleen weight of B10D2F₁ recipients 14 days after transfer of 5–6×10⁷ lymphoid cells from (B10.D2×DBA/2)×B10.D2 backcross mice either homozygous (B/B) or heterozygous (B/D) at the D1Mit150 linkage marker. Probability values were calculated by Mann–Whitney comparison of the indicated groups.

Figure 5

Spleen weight of B10D2F₁ recipients 14 days after transfer of 5–6×10⁷ lymphoid cells from (B10.D2×DBA/2)×B10.D2 backcross mice either homozygous or heterozygous at the D1Mit150 and D4Mit42 linkage markers. Cross markings indicate the mean spleen weight ±1 SE. Probability values were calculated by Mann–Whitney comparison of the indicated groups.

Figure 4

Likelihood plot obtained for Chromosome 1 using the Map Manager QT linkage analysis program.¹⁹ Significance levels were calculated using the permutation test method of Churchill & Doerge,¹⁸ as implemented in the Map Manager QT linkage analysis software.¹⁹ This method indicated that, for the data set used, LOD scores greater than 6·0 are significant at the P = 0·05 level (indicated as ‘Significant’), while LOD scores greater than 12·1 are significant at the P = 0·001 level (indicated as ‘Highly Significant’). cM values represent distance from the centromere as given in the Mouse Genome Database.²³