An inflammatory checkpoint regulates recruitment of graft-versus-host reactive T cells to peripheral tissues

Chakraverty, Ronjon; Côté, Daniel; Buchli, Jennifer; Cotter, Pete; Hsu, Richard; Zhao, Genshi; Sachs, Teviah E.; Pitsillides, Costas; Bronson, Roderick T.; Means, Terry K.; Lin, Charles P.; Sykes, Megan

doi:10.1084/jem.20060376

Cited by 168 publications

(181 citation statements)

References 58 publications

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“…Finally, the observed capacity of adapted T cells to condition innate immune response to LPS suggest that stimulation of TLR signaling by opportunistic infection could trigger deleterious inflammatory reaction in bone marrow-transplanted patients (27). This hypothesis is also supported by the observation that bone marrow-transplanted mice with stable mixed blood chimerism exhibit a high sensitivity to LPS challenge (28,29). It remains to be determined whether this situation results from the activity of T cells adapted to recipient's mHA.…”

Section: Figurementioning

confidence: 50%

Reviving Function in CD4+ T Cells Adapted to Persistent Systemic Antigen

Rivas

Weatherly

Hazzan

et al. 2009

The Journal of Immunology

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In bone marrow-transplanted patients, chronic graft-versus-host disease is a complication that results from the persistent stimulation of recipient minor histocompatibility Ag (mHA)-specific T cells contained within the graft. In this study, we developed a mouse model where persistent stimulation of donor T cells by recipient’s mHA led to multiorgan T cell infiltration. Exposure to systemic mHA, however, deeply modified T cell function and chronically stimulated T cells developed a long-lasting state of unresponsiveness, or immune adaptation, characterized by their inability to mediate organ immune damages in vivo. However, analysis of the gene expression profile of adapted CD4+ T cells revealed the specific coexpression of genes known to promote differentiation and function of Th1 effector cells as well as genes coding for proteins that control T cell activity, such as cell surface-negative costimulatory molecules and regulatory cytokines. Strikingly, blockade of negative costimulation abolished T cell adaptation and stimulated strong IFN-γ production and severe multiorgan wasting disease. Negative costimulation was also shown to control lethal LPS-induced toxic shock in mice with adapted T cells, as well as the capacity of adapted T cells to reject skin graft. Our results demonstrate that negative costimulation is the molecular mechanism used by CD4+ T cells to adapt their activity in response to persistent antigenic stimulation. The effector function of CD4+ T cells that have adapted to chronic Ag presentation can be activated by stimuli strong enough to overcome regulatory signals delivered to the T cells by negative costimulation.

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Section: Figurementioning

confidence: 50%

Reviving Function in CD4+ T Cells Adapted to Persistent Systemic Antigen

Rivas

Weatherly

Hazzan

et al. 2009

The Journal of Immunology

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“…One final factor likely contributing to the development of lethal X-GVHD in irradiated NOD/SCID-β2m null mice is the probable increased trafficking of xenoreactive huT cells to GVHD target tissues following total body irradiation. Indeed, Chakraverty et al [59] recently showed in a murine allogeneic transplant model that irradiation-induced tissue inflammation is a prerequisite for the migration of alloreactive T cells to GVHD target tissues and the induction of GVHD.…”

Section: Discussionmentioning

confidence: 99%

Factors affecting human T cell engraftment, trafficking, and associated xenogeneic graft-vs-host disease in NOD/SCID β2mnull mice

Nervi

Rettig

Ritchey

et al. 2007

Experimental Hematology

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Objective-Graft-versus-host disease (GVHD) is the major cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation. Models of immunodeficient mice that consistently and efficiently reconstitute with xenoreactive human T cells would be a valuable tool for the in vivo study of GVHD, as well as other human immune responses.Materials and Methods-We developed a consistent and sensitive model of human GVHD by retro-orbitally injecting purified human T cells into sublethally irradiated NOD/SCID-β2m null recipients. In addition, we characterized for the first time the trafficking patterns and expansion profiles of xenoreactive human T cells in NOD/SCID-β2m null recipients using in vivo bioluminescence imaging.Results-All NOD/SCID-β2m null mice conditioned with 300 cGy of total body irradiation and injected with 1 × 10 7 human T cells exhibited human T cell engraftment, activation, and expansion, with infiltration of multiple target tissues and a subsequent greater than 20% loss of pretransplant body weight. Importantly, histological examination of the GVHD target tissues revealed changes consistent with human GVHD. Furthermore, we also showed by in vivo bioluminescence imaging that the development of lethal GVHD in the NOD/SCID-β2m null recipients was dependent upon the initial retention and early expansion of human T cells in the retroorbital sinus cavity.Conclusion-Our NOD/SCID-β2m null mouse model provides a system to study the pathophysiology of acute GVHD induced by human T cells and aids in the development of more effective therapies for human GVHD.

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“…In addition, T cells are important contributors to pulmonary toxicity and T-cell depletion can reduce this toxicity, which is especially relevant for Hurler patients. [25][26][27] Some centers might be reluctant to give pre-emptive DLI because of its potential to trigger GVHD. The reported series represents an investigational approach.…”

Section: Discussionmentioning

confidence: 99%

Allogeneic blood SCT for children with Hurler's syndrome: results from the German multicenter approach MPS-HCT 2005

Sauer

Meissner

Fuchs

et al. 2008

Bone Marrow Transplant

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Hurler's syndrome is an inborn error of mucopolysaccharide metabolism leading to premature death in childhood. Allogeneic hematopoietic SCT can achieve long-term survival by correcting the enzymatic deficiency. In an attempt to improve long-term engraftment and to reduce regimen-related toxicity (RRT), a prospective multicenter approach was initiated in Germany using a fludarabinebased radiation-free preparative regimen. Between 2001 and 2008, 12 children were enrolled. Median age at SCT was 14 months (range, 4-31 months). The conditioning regimen contained fludarabine, BU, melphalan and antithymocyte globulin. CD34 positively selected PBSC were used in 10 children with a matched unrelated donor. Median cell dose was 24.6 Â 10 6 CD34 þ cells per kg (range 10.0-54.8). Two children with a matched sibling donor received non-manipulated BM. Donor lymphocyte infusions were given in 6/12 children for mixed hematopoietic chimerism. At a median follow-up of 29 months (range 2-85 months), all children engrafted and have either stabilized or improved neurological function. In total, 12/12 patients showed donor-derived engraftment with 9/12 having full and 3/12 having mixed hematopoiesis. One developed acute GVHD Xgrade II. RRT Xgrade II was observed in two patients.

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An inflammatory checkpoint regulates recruitment of graft-versus-host reactive T cells to peripheral tissues

Cited by 168 publications

References 58 publications

Reviving Function in CD4+ T Cells Adapted to Persistent Systemic Antigen

Reviving Function in CD4+ T Cells Adapted to Persistent Systemic Antigen

Factors affecting human T cell engraftment, trafficking, and associated xenogeneic graft-vs-host disease in NOD/SCID β2mnull mice

Allogeneic blood SCT for children with Hurler's syndrome: results from the German multicenter approach MPS-HCT 2005

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