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

Allen, Ruth D.; Dobkins, J A; Harper, Jill M.; Slayback, D L

doi:10.1046/j.1365-2567.1999.00626.x

Cited by 15 publications

(15 citation statements)

References 32 publications

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“…5). The implicated interval on chromosome 1 contains several candidate genes such as Adprt1, which plays a key role in immune reactions, and Tlr5, which is a member of a group of Toll-like receptors involved in the activation of the immune system in response to various pathogens that has been frequently implicated in murine autoimmunity (27,(33)(34)(35)(36)(37)(38). This locus corresponds to a region on human chromosome 1, ϳ30 Mb apart from the D1S498 marker and ϳ60 Mb from the D1S252 marker, that demonstrated linkage ( p ϳ 0.01 and p ϳ 0.0001, respectively) with infection levels by S. mansoni in humans (39).…”

Section: Discussionmentioning

confidence: 99%

Enhanced Egg-Induced Immunopathology Correlates With High IFN-γ in Murine Schistosomiasis: Identification of Two Epistatic Genetic Intervals

Rutitzky

Hernández

Yim

et al. 2005

The Journal of Immunology

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The genetic basis of dissimilar immunopathology development among mouse strains infected with Schistosoma mansoni is not known. We performed a multipoint parametric linkage analysis on a cohort of F2 mice, offspring of brother-sister mating between (high pathology CBA × low pathology BL/6)F1 mice, to examine whether the observed differences in the type of immune response or the extent of hepatic immunopathology are linked to any particular genomic intervals. The F2 mice exhibited cytokine responses and immunopathologies that revealed a statistically significant correlation between prominent egg Ag-stimulated IFN-γ production by mesenteric lymph node cells and hepatic egg granuloma size. Increased IFN-γ production showed suggestive linkage to a dominant CBA locus on chromosome 1 and a recessive CBA locus on chromosome 5; significantly, there was an epistatic interaction between the two IFN-γ loci. An additional locus with suggestive linkage to granuloma formation and a CBA-recessive mode of inheritance was mapped to centromeric chromosome 13. Our analysis identified the first three genetic regions that appear to influence the immunopathology in murine schistosomiasis; however, further congenic dissection studies will furnish a more precise understanding of the genetic control of this disease.

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Section: Discussionmentioning

confidence: 99%

Enhanced Egg-Induced Immunopathology Correlates With High IFN-γ in Murine Schistosomiasis: Identification of Two Epistatic Genetic Intervals

Rutitzky

Hernández

Yim

et al. 2005

The Journal of Immunology

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“…Indeed, our studies have indicated that loci on chromosomes 1 and 2, in the vicinity of the Mtv7 and IL-1 loci respectively, influence GVHD development in the B6D2F1 model. [33][34][35] The differential outcome of GVHD in the B6D2F1 model is thought to be due to differential activation of Figure 1 The B6D2F1 parent→F1 murine GVHD model. In this model, transfer of parental strain C57BL/6 lymphoid cells into (C57BL/6 × DBA/2)F1 (ie, B6D2F1) recipients results in acute GVHD whereas transfer of parental strain DBA/2 lymphoid cells into B6D2F1 recipients results in chronic GVHD.…”

Section: Quantity Vs Quality Of T Cell Activationmentioning

confidence: 99%

“…In that model, we were able to show that the severity of GVHD in a completely MHCmismatched setting depended on the genotype of donor mice at two specific non-MHC loci-one on chromosome 1 and one on chromosome 2. 33,34 Mice with a specific genotype at these loci had a significantly lowered risk of inducing severe acute GVHD, even though they were MHC-mismatched with recipients. 34 This indicates that it is possible to choose donors whose non-MHC genetics will reduce the risk of their cells inducing life-threatening GVHD in recipients, even when there is not a perfect MHC match.…”

Section: Too Many Restrictions On Choosing a Donor?mentioning

confidence: 99%

The new genetics of bone marrow transplantation

2000

Genes Immun

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There is now little doubt that functional immune polymorphism exists and can exert a significant effect on the severity of immunologic disease. Studies in this area are driven by the belief that an understanding of the influence of immune polymorphism on immunologic disease will improve our ability to predict disease occurrence and severity. The usefulness of this information is necessarily limited, however, by the fact that an individual has a fixed genome. If an individual has an allele which predisposes to increased disease severity, there is little we can do, other than treat the disease in that individual in a more aggressive manner or attempt to find preventative therapies. There is, however, one unique immunologic disorder that is an exception to this rule. Graft-versus-host disease (GVHD), the major complication of bone marrow transplantation, is an immunologic reaction mediated, in large part, by donor T cells. It is unique in that it is the only immunologic disorder in which we can choose the genetics of the immune system causing the disorder. In this disease, more than any other, an understanding of the role of immune polymorphism is essential since we could hypothetically use this information to choose a donor whose T cells will not mediate GVHD of life-threatening severity. In this review, I argue that there is highly suggestive evidence that allelic polymorphism in non-MHC genes encoding mediators of the immune response exerts a very significant effect on the severity of GVHD and that typing for such allelic polymorphisms will in future be as important as MHC-typing in choosing an appropriate donor for bone marrow transplantation. Genes and Immunity (2000) 1, 316-320.

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“…23,24 Analysis of the mean maximum percent weight losses in B6D2F1 recipients of B10.D2 BX cells revealed significantly different maximum percent weight losses between recipients of cells from B10.D2 BX mice that were homozygous at the marker D1Mit57 and recipients of cells from B10.D2 BX donors that were heterozygous at D1Mit57 a n = number of donor mice with the genotype given. b Mean ± standard deviation.…”

Section: Linkage Analysismentioning

confidence: 99%

“…[19][20][21][22] We previously identified a locus on chromosome 1 that exerts a major influence on the development of acute GVHD in this model. 23,24 Candidate genes on chromosome 1 include the gene encoding the superantigen Mtv7 and the gene encoding the cell surface molecule CD48. Mtv7 is an endogenous superantigen that can influence negative selection of T cells.…”

mentioning

confidence: 99%

A locus on chromosome 2 influences the development of acute graft-versus-host disease in a murine model

Harper

Slayback

Dobkins

et al. 1999

Bone Marrow Transplant

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Summary:Despite contemporary typing procedures for bone marrow transplantation (BMT), graft-versus-host disease (GVHD) continues to be a major complication of transplants performed between MHC-matched donors and recipients. Although GVHD can be alleviated by T cell depletion, this procedure increases the risk of graft failure and leukemic relapse and therefore is not a solution to the GVHD problem. The high degree of variation in the intensity of GVHD observed in different patients suggests that multiple non-MHC genetic factors influence GVHD severity. We hypothesize that, in addition to minor histocompatibility antigen disparities, polymorphisms in genes encoding immunologic effector molecules may be important factors influencing GVHD development. This study aims to explore this hypothesis by identifying non-MHC genes that influence the outcome of BMT in a murine model. In this model, B10.D2 donor leukocytes cause acute GVHD in (C57BL/6 × DBA/2)F1 (B6D2F1) recipients, whereas DBA/2 donor leukocytes do not. To date, a locus on chromosome 1 has been identified as influencing the severity of GVHD in this model. Our current study shows that a locus on chromosome 2 acts independently of the chromosome 1 locus to also influence GVHD severity in this model. The region of chromosome 2 implicated in our study contains genes encoding ␤ 2 -microglobulin, the minor histocompatibility antigen H-3 and the pro-inflammatory cytokine IL-1.

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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

Cited by 15 publications

References 32 publications

Enhanced Egg-Induced Immunopathology Correlates With High IFN-γ in Murine Schistosomiasis: Identification of Two Epistatic Genetic Intervals

Enhanced Egg-Induced Immunopathology Correlates With High IFN-γ in Murine Schistosomiasis: Identification of Two Epistatic Genetic Intervals

The new genetics of bone marrow transplantation

A locus on chromosome 2 influences the development of acute graft-versus-host disease in a murine model

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