Graft-versus-host-disease-associated lymphoid hypoplasia and B cell dysfunction is dependent upon donor T cell-mediated Fas-ligand function, but not perforin function

Baker, Matthew B.; Riley, Richard L.; Podack, Eckhard R.; Levy, Robert B.

doi:10.1073/pnas.94.4.1366

Cited by 128 publications

(108 citation statements)

References 36 publications

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“…Prior studies have reported lymph node hypoplasia with GVHD (13)(14)(15). In the 1990's, Onoe and Good examined the phenomenon of lymphoid hypoplasia in the setting of subclinical GVHD (4).…”

Section: Discussionmentioning

confidence: 97%

Purified hematopoietic stem cell allografts reconstitute immunity superior to bone marrow

Tsao

Allen

Logronio

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Antigen-specific immune responses are impaired after allogeneic hematopoietic cell transplantation (HCT). The events contributing to this impairment include host hematolymphoid ablation and donor cell regeneration, which is altered by pharmacologic immune suppression to prevent graft-versus-host disease (GVHD). A generally accepted concept is that graft T cell depletion performed to avoid GVHD yields poorer immune recovery because mature donor T cells are thought to be the major mediators of protective immunity early post-HCT. Our findings contradict the idea that removal of mature donor cells worsens immune recovery post-HCT. By transplantation of purified hematopoietic stem cells (HSC) compared with bone marrow (BM) across donor and recipient pairs of increasing genetic disparity, we show that grafts composed of the purified progenitor population give uniformly superior lymphoid reconstitution, both qualitatively and quantitatively. Subclinical GVHD by T cells in donor BM likely caused this lymphodepleting GVHD. We further determined in the major histocompatibility complex (MHC)-mismatched pairs, that T cell restricted proliferative responses were dictated by donor rather than host elements. We interpret these latter findings to show the importance of peripheral antigen presentation in the selection and maintenance of the T cell repertoire.immune reconstitution ͉ mice ͉ T cell selection

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Section: Discussionmentioning

confidence: 97%

Purified hematopoietic stem cell allografts reconstitute immunity superior to bone marrow

Tsao

Allen

Logronio

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…Inflammatory cytokines and direct antihost cytotoxicity are the main pathogenic factors in the induction of GVHD. Because FasL expression is a major cytotoxic mediator for CD4 ϩ T cells (29,30), we examined the role of ICOS costimulation on FasL expression. Our results highlight the fact that ICOS promotes up-regulation of TCR-driven FasL expression on CD4 ϩ T cells.…”

Section: Discussionmentioning

confidence: 99%

“…Fas ligand (FasL) expression and secretion of Th1 cytokines (i.e., IFN-␥ and TNF-␣) are primary effector functions for CD4 ϩ T cells in inducing GVHD (29,30). To further investigate the mechanisms by which ICOS-blockade ameliorates GVHD, we compared surface expression of FasL on CD4 ϩ T cells from WT or ICOSdeficient donors and found that ICOS Ϫ/Ϫ cells expressed significantly lower levels of FasL than WT cells ( p Ͻ 0.02) (Fig.…”

Section: Icos Enhances Effector Functions Of Cd4 ϩ T Cellsmentioning

confidence: 99%

Opposing Effects of ICOS on Graft-versus-Host Disease Mediated by CD4 and CD8 T Cells

Liang

Nurieva

et al. 2006

The Journal of Immunology

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ICOS, a CD28 family member expressed on activated CD4+ and CD8+ T cells, plays important roles in T cell activation and effector function. Here we studied the role of ICOS in graft-vs-host disease (GVHD) mediated by CD4+ or CD8+ T cells in allogeneic bone marrow transplantation. In comparison of wild-type and ICOS-deficient T cells, we found that recipients of ICOS−/− CD4+ T cells exhibited significantly less GVHD morbidity and delayed mortality. ICOS−/− CD4+ T cells had no defect in expansion, but expressed significantly less Fas ligand and produced significantly lower levels of IFN-γ and TNF-α. Thus, ICOS−/− CD4+ T cells were impaired in effector functions that lead to GVHD. In contrast, recipients of ICOS−/− CD8+ T cells exhibited significantly enhanced GVHD morbidity and accelerated mortality. In the absence of ICOS signaling, either using ICOS-deficient donors or ICOS ligand-deficient recipients, the levels of expansion and Tc1 cytokine production of CD8+ T cells were significantly increased. The level of expansion was inversely correlated with the level of apoptosis, suggesting that increased ability of ICOS−/− CD8+ T cells to induce GVHD resulted from the enhanced survival and expansion of those cells. Our findings indicate that ICOS has paradoxical effects on the regulation of alloreactive CD4+ and CD8+ T cells in GVHD.

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“…The body of data demonstrating the deleterious effects of GVHR on BM and lymphoid function (13)(14)(15)(16)(17)(18)(19)(20)(26)(27)(28) is often overlooked or underestimated. We previously reported that even low amounts of T cells cause subclinical, yet lympho-depleting, GVHR (25).…”

Section: Discussionmentioning

confidence: 99%

Allogeneic T cells impair engraftment and hematopoiesis after stem cell transplantation

Müller

Linderman

Florek

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Because of the perception that depleting hematopoietic grafts of T cells will result in poorer immune recovery and in increased risk of graft rejection, pure hematopoietic stem cells (HSC), which avoid the potentially lethal complication of graft-versus-host disease (GVHD), have not been used for allogeneic hematopoietic cell transplantation (HCT) in humans. Ideal grafts should contain HSC plus mature cells that confer only the benefits of protection from pathogens and suppression of malignancies. This goal requires better understanding of the effects of each blood cell type and its interactions during engraftment and immune regeneration. Here, we studied hematopoietic reconstitution post-HCT, comparing grafts of purified HSC with grafts supplemented with T cells in a minor histocompatibility antigen (mHA)-mismatched mouse model. Cell counts, composition, and chimerism of blood and lymphoid organs were evaluated and followed intensively through the first month, and then subsequently for up to 1 yr. Throughout this period, recipients of pure HSC demonstrated superior total cell recovery and lymphoid reconstitution compared with recipients of T cell-containing grafts. In the latter, rapid expansion of T cells occurred, and suppression of hematopoiesis derived from donor HSC was observed. Our findings demonstrate that even early post-HCT, T cells retard donor HSC engraftment and immune recovery. These observations contradict the postulation that mature donor T cells provide important transient immunity and facilitate HSC engraftment.immune reconstitution | graft composition | mice

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Graft-versus-host-disease-associated lymphoid hypoplasia and B cell dysfunction is dependent upon donor T cell-mediated Fas-ligand function, but not perforin function

Abstract: Allogeneic bone marrow transplant recipients often exhibit a graft-versus-host-disease (GVHD )

Cited by 128 publications

References 36 publications

Purified hematopoietic stem cell allografts reconstitute immunity superior to bone marrow

Purified hematopoietic stem cell allografts reconstitute immunity superior to bone marrow

Opposing Effects of ICOS on Graft-versus-Host Disease Mediated by CD4 and CD8 T Cells

Allogeneic T cells impair engraftment and hematopoiesis after stem cell transplantation

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