Identification of an immunodominant mouse minor histocompatibility antigen (MiHA). T cell response to a single dominant MiHA causes graft-versus-host disease.

Perreault, Claude; Jutras, Julie; Roy, Denis; Filep, János G.; Brochu, Sylvie

doi:10.1172/jci118832

Cited by 63 publications

(30 citation statements)

References 38 publications

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“…For complex genetic diseases, the definition of a modifying locus is the same, although genes which contribute to the risk of disease are better classed as disease-predisposing loci, rather than as modifiers, even though they may have some additional effect on the phenotype. Thus, modifiers of complex disease do not have a qualitative effect on the 22 Alpha thalassaemia 23,24 Neurofibromatosis type 1 25 Fragile X 26 Sickle cell anaemia 27 IDDM 28 Graft-versus-host disease [29][30][31] basic disease phenotype, although they have qualitative effects on sub-phenotypes, such as the development of nephropathy in IDDM.…”

Section: What Is a Modifier Locus?mentioning

confidence: 99%

“…It is very probable that a recipient of a transplant with no sequelae will be more likely to be concordant with his or her donor sibling at the modifier locus as compared to those with a poor course. Minor histocompatibility antigens have been shown to segregate in families 30 and immunodominant minor histocompatibility antigens identified in humans and the mouse. 28,29 Taking sibling pairs from both ends of the clinical spectrum offers an opportunity to undertake a combined discordant and concordant type of analysis in order to identify further modifier loci.…”

Section: Alternative Strategies To Identify Modifier Genesmentioning

confidence: 99%

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Modifier genes in humans: strategies for identification

Houlston

Tomlinson

1998

Eur J Hum Genet

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A number of genetic disorders exhibit inter-and intra-familial variability. Understanding the factors that control the expression of disease genes should provide insight into the fundamental disease processes and will have implications for counselling patients. Different mechanisms can account for this variability, including environmental factors, genotype-phenotype correlations and imprinting. There is also evidence that, in a number of genetic diseases, gene expression is under the control of modifier loci. In cases where the biological basis of the genetic disease is understood, any genes involved in the pathogenic process represent candidate modifier genes which can easily be evaluated. Alternatively, modifiers can be identified through approaches such as mouse models. Since modifier genes will generally be common and because of confounding environmental influences, linkage analyses in humans will generally be based upon affected or discordant sib pairs. Discordant sib pairs represent an attractive option for linkage studies, because recurrence rates are high and the reduced survival characteristics associated with severe phenotypes will make the likelihood of obtaining clinical material from two living cases difficult. Furthermore, the use of discordant siblings will select for those siblings which possess sufficient dissimilarity at the modifier locus to overcome any shared environmental influence.

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Section: What Is a Modifier Locus?mentioning

confidence: 99%

Section: Alternative Strategies To Identify Modifier Genesmentioning

confidence: 99%

Modifier genes in humans: strategies for identification

Houlston

Tomlinson

1998

Eur J Hum Genet

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“…[1][2][3][4][5][6][7][8][9] However, under certain conditions, whether clinically relevant minor Ags can induce GVHD in the absence of functional radiosensitive host hematopoietic APCs is not known. [6][7][8]10 Clinical data from MHC-matched BMT show that male recipients from female donors (F3M) are at a greater risk of developing GVHD 9 and show H-Y-specific alloresponses.…”

Section: Introductionmentioning

confidence: 99%

Induction of acute GVHD by sex-mismatched H-Y antigens in the absence of functional radiosensitive host hematopoietic–derived antigen-presenting cells

Toubai

Tawara

Sun

et al. 2012

Blood

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IntroductionAg presentation on radiosensitive host hematopoiesis-derived APCs to the alloreactive donor T cells is considered to be obligatory for the induction of acute GVHD. 1-9 However, under certain conditions, whether clinically relevant minor Ags can induce GVHD in the absence of functional radiosensitive host hematopoietic APCs is not known. [6][7][8]10 Clinical data from MHC-matched BMT show that male recipients from female donors (F3M) are at a greater risk of developing GVHD 9 and show H-Y-specific alloresponses. [11][12][13][14] These clinical data suggest a strong correlation between H-Y Ag disparity and GVHD. However, in the context of HLA-matched clinical F3M BMT, the donors are also likely to be mismatched with the recipients at multiple minor Ags. Therefore, whether H-Y disparity alone is sufficient for causing clinical acute GVHD is not known. The experimental evidence for the causative role of H-Y Ags in GVHD and mortality has not been reported. Furthermore, the relevance of donor T-cell alloreactivity against a single minor Ag and mechanisms of its presentation in causing GVHD are not known. [1][2][3][4][5] Although some studies have suggested that high doses of TCR transgenic (Tg) T cells can cause GVHD, its severity was limited and was in the context of MHC mismatch or against minor Ags with unknown clinical relevance. 15,16 With the use of both H-Y-specific Tg and non-Tg T cells in multiple well-established BM chimeras we demonstrate, in contrast to the existing notion, that presentation of clinically relevant minor H-Y Ag by host radiosensitive hematopoieticderived APCs is not obligatory for induction of acute GVHD. 3,[6][7][8]10,17 Our data further suggest that in the absence of radiosensitive host hematopoietic-derived APCs, when sufficient numbers of alloreactive donor T cells are infused, nonhematopoietic-derived cells such as endothelial and certain epithelial cells activate alloreactive T cells, might induce GVHD. Methods MiceMale and female C57BL/6 (B6, H-2 b , CD45.2 ϩ ), B6 Ly5.2 (H-2 b , CD45.1 ϩ ), and BALB/c (H-2 d ) mice were purchased from The Jackson 17 and MataHari (RAG-1 Ϫ background, CD8 ϩ Tg, H-2 b , CD45.2 ϩ , H-2D b -restricted) mice 18 were obtained from Taconic. All animals were cared for under regulations reviewed and approved by the University Committee on Use and Care of Animals of the University of Michigan, based on University Laboratory Animal Medicine guidelines. Generation of BM chimerasWe administered 1100 cGy total body irradiation ( 137 Cs source) to mice and then injected them intravenously with 5 ϫ 10 6 BM cells with 5 ϫ 10 6 whole spleen cells from donor mice on day Ϫ1. For generating MHC class I-deficient (␤2m-KO) BM chimeras, recipient mice were treated with 200 g of anti-NK1.1 mAb (PK136) on days Ϫ2 and Ϫ1. 6 The peripheral blood from sentinel mice were analyzed for donor chimerism at 3 months and found to show Ͼ 98% donor chimerism in all cell lineages. The CD11c ϩ cells in the splenocytes from these animals also showed Ͼ 95% donor chimerism. BMTBMT...

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“…These results indicate minor Ags, at least with the strain combinations used in this study, do not have a significant role in neonatal graft rejection. Dominant minor Ags in other strains (H60 and B6dom1) have been described that have a significant role in GVHD and may play a role in neonatal graft rejection (34,35).…”

Section: Discussionmentioning

confidence: 99%

Successful Allogeneic Neonatal Bone Marrow Transplantation Devoid of Myeloablation Requires Costimulatory Blockade

Soper

Lessard

Jude

et al. 2003

The Journal of Immunology

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A significant number of nonmalignant, progressive childhood disorders respond to bone marrow transplantation (BMT). Toxic myeloablative pretreatment regimens, graft failure, and graft-vs-host disease complicate the utility of BMT for neonatal treatment. We recently demonstrated high-dose BMT in neonatal animals enables chimeric engraftment without toxic myeloablation. Reagents that block T cell costimulation (anti-CD40L mAb and/or CTLA-4Ig) establish tolerant allogeneic engraftment in adult recipients. Donor lymphocyte infusion (DLI) re-establishes failing grafts and treats malignant relapse via a graft-vs-leukemia response. In this study, we tested the hypothesis that combining these approaches would allow tolerant allogeneic engraftment devoid of myeloablation in neonatal normal and mutant mice with lysosomal storage disease. Tolerant chimeric allogeneic engraftment was achieved before DLI only in the presence of both anti-CD40L mAb and CTLA-4Ig. DLI amplified allografts to full donor engraftment long-term. DLI-treated mice either maintained long-term tolerance or developed late-onset chronic graft-vs-host disease. This combinatorial approach provides a nontoxic method to establish tolerant allogeneic engraftment for treatment of progressive childhood diseases.

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Identification of an immunodominant mouse minor histocompatibility antigen (MiHA). T cell response to a single dominant MiHA causes graft-versus-host disease.

Cited by 63 publications

References 38 publications

Modifier genes in humans: strategies for identification

Modifier genes in humans: strategies for identification

Induction of acute GVHD by sex-mismatched H-Y antigens in the absence of functional radiosensitive host hematopoietic–derived antigen-presenting cells

Successful Allogeneic Neonatal Bone Marrow Transplantation Devoid of Myeloablation Requires Costimulatory Blockade

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