Immunology 1999 96 254–261
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
R. D. ALLEN, J. A. DOBKINS, J. M. HARPER & D. L. SLAYBACK Department of Biology, Indiana University-Purdue
University at Indianapolis, IN, USA
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?F1murine 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.
factors may indeed exist. When (C57BL/10×DBA/2)F1
(B10D2F1) mice (H-2b/d) receive spleen cells from B10.D2
(H-2d) donors, an acute, fatal GVHD develops.9 Conversely,
when B10D2F1mice receive spleen cells from DBA/2 (H-2d)
donors, a protracted, chronic GVHD with features of
the autoimmune syndrome systemic lupus erythematosus
B10.D2?B10D2F1and DBA/2?B10D2F1), the major histoc-
ompatibility complex (MHC) haplotype of the donor is ident-
ical and the MHC disparities being recognized in the host are
identical. Therefore, the different course of GVHD must be
determined by non-MHC factors.
Analysis of cytokine production during the early develop-
ment of GVHD in B10D2F1recipients of either B10.D2 or
DBA/2 spleen cells has provided some evidence suggesting
that the development of acute versus chronic GVHD in this
model reflects the differential predominance of either T helper
1 (Th1) or T helper 2 (Th2) cells, respectively.12–15 If this is
the case, then non-MHC genetic differences between the
B10.D2 and DBA/2 donor strains must determine whether
Th1 or Th2 cells will predominate in this GVH response and
thereby influence the nature of GVHD-associated pathology.
In order to explore the hypothesis that polymorphism in
immunological effector molecules, as well as antigen disparity,
plays a major role in determining the outcome of GVHD, we
are mapping the genetic differences between the B10.D2 and
DBA/2 strains that influence the outcome of GVHD in the
Graft-versus-host disease (GVHD) is a complex process that
is initiated upon recognition of foreign host histocompatibility
antigens by engrafted donor T cells. It has generally been
accepted that the severity of GVHD is dependent on the extent
of disparity between host and donor for major and/or minor
histocompatibility antigens. While there can be little doubt
that a relationship does exist between the severity of GVHD
and the degree of antigen disparity between host and donor,
other factors may also influence the severity and associated
pathology of this syndrome.
Recently, polymorphisms have been identified in a signifi-
cant number of immunological effector molecules. Examples
include a polymorphism in the interleukin-10 (IL-10) gene
promoter,1 polymorphism in the IL-4 gene promoter,2 poly-
morphisms influencing IL-1 activity,3,4 polymorphism in the
IL-2 gene5 and polymorphisms in tumour necrosis factor-a
(TNF-a) and TNF-b.6 A growing number of studies are
reporting links between such immune polymorphisms and the
severity of immunological disease.6–8 It is possible that similar
polymorphisms may also influence the course of GVHD.
At least one murine model indicates that such modifying
Received 6 April 1998; revised 29 July 1998; accepted 29 July 1998.
Correspondence: Dr R. D. Allen, Department of Biology, IUPUI,
723 W. Michigan St., Indianapolis, IN 46202, USA.
© 1999 Blackwell Science Ltd
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© 1999 Blackwell Science Ltd, Immunology, 96, 254–261