Effector Mechanisms in Graft-Versus-Host Disease in Response to Minor Histocompatibility Antigens

Ca, van Els; Bakker, Aleida M.; Ah, Zwinderman; Fe, Zwaan; Jj, van Rood; Goulmy, Els

doi:10.1097/00007890-199007000-00011

Cited by 54 publications

(9 citation statements)

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“…Historically, alloreactive donor T cells have been the primary factor implicated in the pathophysiology of cGVHD. However, a recent randomized trial failed to demonstrate that T cell depletion reduced cGVHD incidence [28]. Therefore, the role of direct T cell mediated allogeneic immune responses in cGVHD is not clear, and there is no strong correlation between the number of minor histocompatibility antigen specific T cells and cGVHD [29,30].…”

Section: Pathophysiologymentioning

confidence: 99%

Chronic Graft-Versus-Host Disease (GVHD) in Children

Baird

Cooke

Schultz

2010

Pediatric Clinics of North America

119

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Five-year survival rates for childhood cancer now exceed 80% and with the significant progress made by the transplant community in developing less toxic conditioning regimens and in the treatment of posttransplant complications, allo-hematopoietic stem cell transplantation (HSCT) contributes significantly to that population of long-term survivors. In this context, the acute and long-term toxicities of chronic graft-versus-host disease (cGVHD) have an ever-increasing effect on organ function, quality of life, and survival; patients and families who initially felt great relief to be cured from the primary disease, now face the challenge of a chronic debilitating illness for which preventative and treatment strategies are suboptimal. Hence, the development of novel strategies that reduce and or control cGVHD, preserve graft-versus-tumor effects, facilitate engraftment and immune reconstitution, and enhance survival after allo-HSCT represents one of the most significant challenges facing physician-scientists and patients.

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Section: Pathophysiologymentioning

confidence: 99%

Chronic Graft-Versus-Host Disease (GVHD) in Children

Baird

Cooke

Schultz

2010

Pediatric Clinics of North America

119

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“…There is strong evidence that GVHD is the result of donor T-cell recognition of endogenous minor (MiHC) or major (MHC) histocompatibility antigens expressed by recipient cells [1,2]. In humans, GVHD secondary to MiHC disparity results in clonal proliferation of donor T-cells in vivo [3], and the presence of donor-derived CD4 + and CD8 + T-cells in blood and marrow transplantation (BMT) patients correlates with the development of GVHD [4][5][6][7]. The primary therapeutic approach to control of GVHD is the use of immunosuppressive agents.…”

Section: Introductionmentioning

confidence: 99%

Chloroquine prevention of murine MHC-disparate acute graft-versus-host disease correlates with inhibition of splenic response to CpG oligodeoxynucleotides and alterations in T-cell cytokine production

Schultz

Hsiao

et al. 2002

Biology of Blood and Marrow Transplantation

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The 4-aminoquinolines, chloroquine and hydroxychloroquine, are established, with a 52% response rate, as therapy for human steroid-refractory GVHD after BMT. Chloroquine affects numerous mechanisms that play a role in GVHD, including inhibition of major histocompatibility complex (MHC) class II antigen presentation, cytokine production, and antigen-presenting cell activation by bacterially derived CpG oligodeoxynucleotides (ODNs). Using an MHC-disparate murine model, we evaluated the effect of chloroquine treatment on the development of acute GVHD. We assessed the effect of chloroquine on the immunostimulatory responses induced by CpG ODNs after BMT. We also evaluated the impact of chloroquine on cytokine-producing populations known to affect GVHD, including CD4+ and CD8+ T-cell and CD3(+)/NK1.1(+) natural killer T-cell (NKT cell) populations. Twelve (86%) of 14 mice receiving phosphate-buffered saline solution (PBS) developed lethal GVHD; only 4 (29%) of 14 mice receiving chloroquine 20 mg/kg 3 times per week developed lethal GVHD (P < .01). Chloroquine significantly suppressed CpG ODN-induced splenic proliferation and interleukin 6 (IL-6) production associated with GVHD. Chloroquine suppressed CD8+ T-cell production of IL-2 and IL-4 associated with GVHD in this model and maintained an early expansion (day 7) of splenic NKT cells. These results indicate that the 4-aminoquinolines are effective in therapy for or prevention of acute GVHD secondary to MHC disparities. Chloroquine actions may include inhibition of CpG ODN augmentation of GVHD. Other mechanisms involved may include suppression of CD8+ T-cell production of IL-2 and IL-4 and an increase in NKT cells associated with GVHD inhibition by chloroquine.

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“…The role of mHag-specific CTLs in GvHD pathogenesis has been addressed [13][14][15][16][17][18][19][20] . In some studies, increased host-reactive CTL or T helper-cell frequencies were associated with GvHD (refs.…”

mentioning

confidence: 99%

“…13,14,20); other studies could not show a correlation between GvHD and host reactive CTL precursor frequencies in PBMCs obtained after BMT (refs. [15][16][17][18]. A previous analysis of the effect of a disparity in mHags HA-1, -2, -4 and -5 between HLA-identical bone marrow donor and recipients demonstrated a significant correlation between mHag mismatch and development of GvHD grade II or more in adult patients 4 .…”

mentioning

confidence: 99%

Tetrameric HLA class I–minor histocompatibility antigen peptide complexes demonstrate minor histocompatibility antigen-specific cytotoxic T lymphocytes in patients with graft-versus-host disease

Mutis

Gillespie

Schrama

et al. 1999

Nat Med

Self Cite

252

149

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Graft-versus-host disease (GvHD) is a chief complication of allogeneic bone marrow transplantation. In HLA-identical bone marrow transplantation, GvHD may be induced by disparities in minor histocompatibility antigens (mHags) between the donor and the recipient, with the antigen being present in the recipient and not in the donor. Cytotoxic T lymphocytes (CTLs) specific for mHags of the recipients can be isolated from the blood of recipients with severe GvHD (ref. 3). A retrospective study demonstrated an association between mismatch for mHags HA-1, -2, -4 and -5 and the occurrence of GvHD in adult recipients of bone marrow from HLA genotypically identical donors. Tetrameric HLA-peptide complexes have been used to visualize and quantitate antigen-specific CTLs in HIV-infected individuals and during Epstein-Barr virus and lymphocytic choriomeningitis virus infections. Here we show the direct ex vivo visualization of mHag-specific CTLs during GvHD using tetrameric HLA-class and I-mHag HA-1 and HY peptide complexes. In the peripheral blood of 17 HA-1 or HY mismatched marrow recipients, HA-1- and HY-specific CTLs were detected as early as 14 days after bone marrow transplantation. The tetrameric complexes demonstrated a significant increase in HA-1- and HY-specific CTLs during acute and chronic GvHD, which decreased after successful GvHD treatment. HLA class I-mHag peptide tetramers may serve as clinical tools for the diagnosis and monitoring of GvHD patients.

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Effector Mechanisms in Graft-Versus-Host Disease in Response to Minor Histocompatibility Antigens

Cited by 54 publications

References 0 publications

Chronic Graft-Versus-Host Disease (GVHD) in Children

Chronic Graft-Versus-Host Disease (GVHD) in Children

Chloroquine prevention of murine MHC-disparate acute graft-versus-host disease correlates with inhibition of splenic response to CpG oligodeoxynucleotides and alterations in T-cell cytokine production

Tetrameric HLA class I–minor histocompatibility antigen peptide complexes demonstrate minor histocompatibility antigen-specific cytotoxic T lymphocytes in patients with graft-versus-host disease

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