Oral graft-versus-host disease and programmed cell death: Pathogenetic and clinical correlates

After hematopoietic stem cell transplantation, the persistence and expansion of grafted mature postthymic T cells allow both transfer of donor immunologic memory and generation of a diverse T repertoire. This thymic-independent process, which is particularly important in humans, because most transplant recipients present severe thymus atrophy, is impaired by graft-versus-host disease (GVHD). The goal of this study was to decipher how GVHD influences the fate of grafted postthymic T cells. Two major findings emerged. First, we found that, after a brisk proliferation phase, alloreactive antihost T cells underwent a massive activation-induced cell death (AICD). For both CD4+ and CD8+ T cells, the Fas pathway was found to play a major role in this AICD: alloreactive T cells upregulated Fas and FasL, and AICD of antihost T cells was much decreased in the case of lpr (Fas-deficient) donors. Second, whereas non–host-reactive donor T cells neither upregulated Fas nor suffered apoptosis when transplanted alone, they showed increased membrane Fas expression and apoptosis when coinjected with host-reactive T cells. We conclude that GVHD-associated AICD of antihost T cells coupled with bystander lysis of grafted non–host-reactive T cells abrogate immune reconstitution by donor-derived postthymic T lymphocytes. Furthermore, we speculate that massive lymphoid apoptosis observed in the acute phase of GVHD might be responsible for the occurrence of autoimmunity in the chronic phase of GVHD.

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Extracorporeal photophoresis increases sensitivity of monocytes from patients with graft-versus-host disease to HLA-DR–mediated cell death

Transfusion ◽

10.1111/j.1537-2995.2007.01502.x ◽

2007 ◽

Vol 0 (0) ◽

pp. 071005074756006-??? ◽

Cited By ~ 2

Author(s):

Niclas Setterblad ◽

Frédéric Garban ◽

Roman Weigl ◽

Eric Assier ◽

Philippe Drillat ◽

...

Keyword(s):

Cell Death ◽

Graft Versus Host Disease ◽

Host Disease ◽

Graft Versus Host ◽

Hla Dr

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Targeting Syk-activated B cells in murine and human chronic graft-versus-host disease

Blood ◽

10.1182/blood-2014-08-595470 ◽

2015 ◽

Vol 125 (26) ◽

pp. 4085-4094 ◽

Cited By ~ 57

Author(s):

Ryan Flynn ◽

Jessica L. Allen ◽

Leo Luznik ◽

Kelli P. MacDonald ◽

Katelyn Paz ◽

...

Keyword(s):

Cell Death ◽

B Cells ◽

B Cell ◽

Graft Versus Host Disease ◽

Cell Activation ◽

B Cell Activation ◽

Host Disease ◽

Graft Versus Host ◽

Key Points ◽

Syk Inhibitor

Key Points Syk is required for increased B-cell activation and cGVHD generation and maintenance. The Syk inhibitor fostamatinib can treat murine cGVHD and increase human cGVHD B-cell death.

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Murine acute graft-versus-host disease can be prevented by depletion of alloreactive T lymphocytes using activation-induced cell death

Blood ◽

10.1182/blood.v99.8.3041 ◽

2002 ◽

Vol 99 (8) ◽

pp. 3041-3049 ◽

Cited By ~ 51

Author(s):

Udo F. Hartwig ◽

Michael Robbers ◽

Claudia Wickenhauser ◽

Christoph Huber

Keyword(s):

T Cells ◽

Cell Death ◽

T Lymphocytes ◽

Graft Versus Host Disease ◽

Allogeneic Bone ◽

Host Disease ◽

Graft Versus Host ◽

Activation Induced Cell Death ◽

Alloreactive T Cells ◽

Graft Versus Leukemia

Abstract Depletion of T lymphocytes from allogeneic bone marrow transplants successfully prevents the development of graft-versus-host disease (GvHD) but is associated with impaired engraftment, immunosuppression, and abrogation of the graft-versus-leukemia effect. We therefore explored the possibility of selectively eliminating alloreactive T cells by CD95/CD95L–mediated activation-induced cell death (AICD) in a major histocompatibility complex allogeneic murine model system. Activation of resting or preactivated T lymphocytes from C3H/HeJ (H-2k) mice was induced with irradiated BALB/cJ (H-2d) mouse-derived stimulators. Substantial decrease (≥ 80%) of proliferative and lytic responses by activated alloreactive T cells was subsequently achieved by incubating the mixed lymphocyte culture with an agonistic monoclonal antibody to CD95, and residual T cells recovered did not elicit alloreactivity upon challenge to H-2d. Depletion of alloreactive T lymphocytes by AICD was specific because reactivity to an I-Ad–restricted ovalbumin (OVA) peptide by OVA-specific CD4+ T cells mixed into the allogeneic T-cell pool and subjected to induction of AICD in the absence of OVA peptide could be preserved. Adoptive transfer of donor-derived allogeneic T lymphocytes, depleted from alloreactive T cells by AICD in vitro, in the parent (C3H/He) to F1 (C3H/He × BALB/c) GvHD model prevented lethal GvHD. The results presented suggest that alloreactive T cells can effectively be depleted from allogeneic T cells by induction of AICD to prevent GvHD and might introduce a new strategy for the separation of GvH-reactive T cells and T cells mediating antiviral and possibly graft-versus-leukemia effects.

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111Selective depletion of human GVH-reactive T-cells by anti-CD95 mediated activation-induced cell death or via the T-cell activation antigen CD69 for preventing graft-versus-host disease in allo-BMT

Biology of Blood and Marrow Transplantation ◽

10.1016/s1083-8791(03)80112-x ◽

2003 ◽

Vol 9 (2) ◽

pp. 98

Author(s):

M. Nonn ◽

I. Tubbe ◽

C. Huber ◽

U.F. Hartwig

Keyword(s):

T Cells ◽

Cell Death ◽

T Cell ◽

T Cell Activation ◽

Graft Versus Host Disease ◽

Cell Activation ◽

Host Disease ◽

Graft Versus Host ◽

Activation Induced Cell Death ◽

Activation Antigen

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CD95 ligand-dependant endothelial cell death initiates oral mucosa damage in a murine model of acute graft versus host disease

Laboratory Investigation ◽

10.1038/labinvest.3700541 ◽

2007 ◽

Vol 87 (5) ◽

pp. 417-429 ◽

Cited By ~ 19

Author(s):

Christophe Deschaumes ◽

Laurence Verneuil ◽

Marjan Ertault-Daneshpouy ◽

Homa Adle-Biassette ◽

Françoise Galateau ◽

...

Keyword(s):

Cell Death ◽

Endothelial Cell ◽

Oral Mucosa ◽

Graft Versus Host Disease ◽

Murine Model ◽

Host Disease ◽

Graft Versus Host ◽

Cd95 Ligand ◽

Endothelial Cell Death ◽

Acute Graft

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Massive Activation-Induced Cell Death of Alloreactive T Cells With Apoptosis of Bystander Postthymic T Cells Prevents Immune Reconstitution in Mice With Graft-Versus-Host Disease

Blood ◽

10.1182/blood.v94.2.390 ◽

1999 ◽

Vol 94 (2) ◽

pp. 390-400 ◽

Cited By ~ 71

Author(s):

Sylvie Brochu ◽

Benjamin Rioux-Massé ◽

Jean Roy ◽

Denis-Claude Roy ◽

Claude Perreault

Keyword(s):

T Cells ◽

Cell Death ◽

Graft Versus Host Disease ◽

Immune Reconstitution ◽

Chronic Phase ◽

Hematopoietic Stem ◽

Host Disease ◽

Graft Versus Host ◽

Activation Induced Cell Death ◽

Alloreactive T Cells

Abstract After hematopoietic stem cell transplantation, the persistence and expansion of grafted mature postthymic T cells allow both transfer of donor immunologic memory and generation of a diverse T repertoire. This thymic-independent process, which is particularly important in humans, because most transplant recipients present severe thymus atrophy, is impaired by graft-versus-host disease (GVHD). The goal of this study was to decipher how GVHD influences the fate of grafted postthymic T cells. Two major findings emerged. First, we found that, after a brisk proliferation phase, alloreactive antihost T cells underwent a massive activation-induced cell death (AICD). For both CD4+ and CD8+ T cells, the Fas pathway was found to play a major role in this AICD: alloreactive T cells upregulated Fas and FasL, and AICD of antihost T cells was much decreased in the case of lpr (Fas-deficient) donors. Second, whereas non–host-reactive donor T cells neither upregulated Fas nor suffered apoptosis when transplanted alone, they showed increased membrane Fas expression and apoptosis when coinjected with host-reactive T cells. We conclude that GVHD-associated AICD of antihost T cells coupled with bystander lysis of grafted non–host-reactive T cells abrogate immune reconstitution by donor-derived postthymic T lymphocytes. Furthermore, we speculate that massive lymphoid apoptosis observed in the acute phase of GVHD might be responsible for the occurrence of autoimmunity in the chronic phase of GVHD.

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ATP Acts as Danger Associated Molecular Pattern and Enhances Acute Graft-Versus-Host Disease Severity Via P2×7-R.

Blood ◽

10.1182/blood.v114.22.1336.1336 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1336-1336

Author(s):

Konrad Wilhelm ◽

Tobias Müller ◽

Jayanthi Ganesan ◽

Christoph Dürr ◽

Ulrike Gerlach ◽

...

Keyword(s):

T Cells ◽

Cell Death ◽

Disease Severity ◽

Graft Versus Host Disease ◽

Purinergic Receptors ◽

Conflicts Of Interest ◽

B Cell Lymphoma ◽

Stress Injury ◽

Host Disease ◽

Graft Versus Host

Abstract Abstract 1336 Poster Board I-358 Conditioning prior allogeneic hematopoietic cell transplantation causes local tissue injury. Cellular molecules that are released upon cell stress, injury or cell death can act as potent danger associated molecular patterns (DAMP). Nucleotides like ATP are ideal candidates to serve as such indicators of cell damage, since they are present in the extracellular environment in the nanomolar range under physiological conditions but are released upon unphysiological cell death which causes activation of purinergic receptors. The role of purinergic signaling in alloantigen driven immune responses such as graft-versus-host disease (GvHD) is unclear. We found that ATP levels in the peritoneal fluid increased when GvHD was present in human and mice. Detection of extracellular ATP with a luciferase based in vivo detection system demonstrated early ATP release from the gastrointestinal tract. Blockade of multiple purinergic receptors on T cells or ATP neutralization during GvHD development reduced disease severity and proinflammatory cytokine production significantly. Gene expression analysis of different P2R in GvHD target organs identified the P2X7(R)receptor to be increasingly expressed. P2X7R−/− recipients developed less severe GvHD as compared to wildtype mice. This was paralleled by the induction of STAT5 signaling with increased numbers of Foxp3 positive regulatory T cells while STAT1 phosphorylation and IFN-γ production was reduced. Despite P2X7R blocking, T cells were still able to reconstitute the lymphoid compartment with a polyclonal intact TCR repertoire analyzed by spectratyping DNA sequence analyses of the CDR3 region and to reject established B-cell lymphoma. Therefore, DAMPs such as endogenous nucleotides may not be required for anti-tumor activity but dominantly trigger acute GvHD. Blockade or genetic deficiency of P2X7R in BMT recipients conferred GvHD protection without loss of GvL effects, which has important clinical implications given the availability of P2X7R inhibitors. Disclosures No relevant conflicts of interest to declare.

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Exploiting Cell Death Pathways for Inducible Cell Elimination to Modulate Graft-versus-Host-Disease

Biomedicines ◽

10.3390/biomedicines5020030 ◽

2017 ◽

Vol 5 (4) ◽

pp. 30 ◽

Cited By ~ 3

Author(s):

◽

Keyword(s):

Cell Death ◽

Graft Versus Host Disease ◽

Host Disease ◽

Graft Versus Host ◽

Cell Death Pathways

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