Transient control of a virus-induced immunopathology by genetic immunosuppression

Boyer, Olivier; Cohen, José L.; Bellier, Bertrand; Thomas‐Vaslin, Véronique; Klatzmann, David; Saron, Marie-Françoise

doi:10.1038/sj.gt.3301276

Cited by 5 publications

(3 citation statements)

References 53 publications

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“…To identify the origin of T-cell reconstitution after BMT-ie, central thymic production versus peripheral expansion of mature donor T cells-we generated double-transgenic mice coexpressing the TK enzyme in CD4 ϩ and CD8 ϩ T cells 18 and an hCD4 marker molecule at the surface of CD4 ϩ T cells. 13 T cells from [hCD4 ϫ TK] double-transgenic mice (FVB, H-2 q ) were infused together with TCD BM cells from wild-type mice (FVB) in lethally irradiated syngeneic or allogeneic recipients.…”

Section: Experimental Modelmentioning

confidence: 99%

Suicide gene therapy of graft-versus-host disease: immune reconstitution with transplanted mature T cells

Cohen

Boyer

Klatzmann

2001

Blood

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After allogeneic hematopoietic stem cell transplantation (HSCT), mature transplanted T cells play a major role in restoration of the immune system. However, they can also induce a life-threatening complication: graftversus-host disease (GVHD). Suicide gene therapy of GVHD aims to selectively eliminate alloreactive T cells mediating GVHD while sparing nonalloreactive T cells that should contribute to immune reconstitution. It was demonstrated previously that treatment with ganciclovir (GCV) can control GVHD in mice by killing donor T cells engineered to express the thymidine kinase (TK) suicide gene. TK allows phosphorylation of nontoxic GCV into triphosphate GCV, which is selectively toxic for dividing cells. Thus, in the TK-GCV system, the specificity of cell killing depends on the cycling status of TK T cells rather than allogeneic recognition. This is a potential drawback because in recipients of lymphopenic allogeneic HSCT, alloreactive and homeostatic signals drive the proliferation of donor T cells. It is shown here that the onset of alloreactive T-cell division occurs earlier than that of nonalloreactive T cells, thus establishing a time frame for GCV administration. A 7-day GCV treatment initiated at the time of HSCT allowed efficient prevention of GVHD, while sparing a pool of nondividing donor TK T cells. These cells later expanded and contributed to the replenishment of the recipient immune system with a diversified T-cell receptor repertoire. These results provide a rationale for designing the therapeutic scheme when using TK-GCV suicide gene therapy in allogeneic HSCT. IntroductionThe prognosis for a patient who undergoes allogeneic hematopoietic stem cell transplantation (HSCT) is influenced by the presence in the recipient of postthymic peripheral donor T cells that improve engraftment 1 and T-cell reconstitution 2 and that provide a graft-versusleukemia (GVL) effect. 3 In adult patients, such T cells mainly arise from the persistence and expansion of infused donor T cells. 2,4 Indeed, the differentiation of donor HSCs in the adult recipient thymus is inefficient, as illustrated by the observation that adults grafted with T-cell-depleted (TCD) bone marrow (BM) often remain immunodeficient for several months after transplantation. 4 In addition to the beneficial effects of infused donor T cells, activation of those specific for recipient alloantigens often results in a life-threatening complication: graft-versus-host disease (GVHD). 5 Thus, a major challenge of allogeneic HSCT is to achieve good T-cell reconstitution without GVHD.A strategy for genetic immunosuppression based on conditional elimination of dividing donor T cells expressing the herpes simplex type 1 thymidine kinase (TK) suicide gene was recently developed (for review, see Cohen et al). 6 TK allows phosphorylation of the nontoxic prodrug ganciclovir (GCV) into triphosphate GCV, which, by blocking DNA elongation, is toxic for dividing cells. Hence, on activation and division, TK T cells become sensitive to GCV. 7,8 We previously vali...

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Section: Experimental Modelmentioning

confidence: 99%

Suicide gene therapy of graft-versus-host disease: immune reconstitution with transplanted mature T cells

Cohen

Boyer

Klatzmann

2001

Blood

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“…Using these mice, we showed that the transient depletion of dividing T cells by GCV (i) controls T-cell-mediated immune diseases involving alloreactive and pathogenic T cells (22)(23)(24)(25)(26); (ii) induces long-term, specific and robust tolerance to vascularized allogeneic heart grafts (27) or delayed rejection of self-vascularized skin and heart (28); (iii) and disrupts immunological memory maintenance (29). Here we show, in allogeneic pancreatic islet transplantation, that tolerance induction is mediated by a progressive expansion of Treg.…”

Section: T-cell Dynamics and Transplantation Tolerancementioning

confidence: 99%

Transient Depletion of Dividing T Lymphocytes in Mice Induces the Emergence of Regulatory T Cells and Dominant Tolerance to Islet Allografts

Giraud

Barrou²,

Sebillaud³

et al. 2008

American Journal of Transplantation

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“…Used in pathological situations, the conditional pharmacogenetic immunosuppression induced by the TK/GCV system allows to (i) transiently control LCMV infection (Boyer, Cohen et al 2000). (ii) control GVHD (Cohen, Boyer et al 1997;Cohen, Saron et al 2000;Cohen, Boyer et al 2001).…”

Section: Specific Transient Depletion Of Dividing T Cells To Control mentioning

confidence: 99%

Immunodepression and Immunosuppression During Aging

Thomas‐Vaslin¹,

Six²,

Pham³

et al. 2012

Immunosuppression - Role in Health and Diseases

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Transient control of a virus-induced immunopathology by genetic immunosuppression

Cited by 5 publications

References 53 publications

Suicide gene therapy of graft-versus-host disease: immune reconstitution with transplanted mature T cells

Suicide gene therapy of graft-versus-host disease: immune reconstitution with transplanted mature T cells

Transient Depletion of Dividing T Lymphocytes in Mice Induces the Emergence of Regulatory T Cells and Dominant Tolerance to Islet Allografts

Immunodepression and Immunosuppression During Aging

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