Rapamycin Prolongs Susceptibility of Responding T Cells to Tolerance Induction by CD8+ Veto Cells

Anderson, Kathryn B.; Zimring, James C.

doi:10.1097/01.tp.0000185302.38890.6b

Cited by 13 publications

(8 citation statements)

References 24 publications

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“…Our results seem to be also in line with tolerance induction by veto CTLs out of the context of BM allografting, namely for CTLs presensitized against viral Ags which were found to be as susceptible in vitro to veto cell inhibition as their naive counterparts (43). However, this veto activity on presenstized effectors directed against viral Ags has to be confirmed in vivo.…”

Section: Discussionsupporting

confidence: 84%

“…Thus, effector T cells that might have escaped deletion by the veto cells could still be eliminated by rapamycin. Moreover, Anderson et al (43) suggested that rapamycin prevents the responding cells from differentiating into fully activated CTLs and that the point of inhibition precedes the loss of a veto sensitive phenotype.…”

Section: Discussionmentioning

confidence: 99%

“…Considering that Anderson et. al (43) showed recently that addition of rapamycin extends the window during which responding cells are susceptible to deletion by veto cells, it would be interesting to test the possibility that blockade of the CD27-CD70 costimulatory pathway might be synergistic with veto CTLs, so as to potentially substitute the need for treatment with rapamycin.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Tolerance Induction in Presensitized Bone Marrow Recipients by Veto CTLs: Effective Deletion of Host Anti-Donor Memory Effector Cells

Reich-Zeliger

Bachar-Lustig

Bar-Ilan

et al. 2007

The Journal of Immunology

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Veto cells have been defined as cells capable of inducing apoptosis of effector CD8 cells recognizing their disparate MHC Ags. Tolerance induced by donor-type veto cells is desirable, because it is restricted to depletion of anti-donor clones without depletion of other immune specificities. It has been shown that anti-third party CTLs exhibit marked veto activity with reduced capacity to induce graft-vs-host disease, when tested on naive effector cells. However, presensitized T cells could play an important role in graft rejection, and therefore, their sensitivity to veto cells could be critical to the implementation of the latter cells in bone marrow transplantation. To address this question, we compared naive and presensitized TCR transgenic effector CD8 T cells, bearing a TCR against H-2d. Both cell types exhibited similar predisposition to killing by veto CTLs in vitro, and this killing was dependent in both cell types on Fas-FasL signaling as shown by using Fas-deficient CD8 T cells from (lprx2c) F1 mice. When tested in a stringent mouse model, in which bone marrow rejection is mediated by adoptively transferred host type T cells into lethally irradiated recipients, veto CTLs were equally effective in overcoming rejection of naive or presensitized host T cells.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Tolerance Induction in Presensitized Bone Marrow Recipients by Veto CTLs: Effective Deletion of Host Anti-Donor Memory Effector Cells

Reich-Zeliger

Bachar-Lustig

Bar-Ilan

et al. 2007

The Journal of Immunology

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“…45 This reduced in vivo responsiveness stemmed from the lack of ability of veto CTLs, which are effector cells that home to the periphery, to co-localize with host anti-donor CTLp in the lymph nodes (LNs), before the latter differentiate into effector cells, become unsusceptible to the veto effect and instigate graftversus-host response. 57 This was nicely demonstrated by comparing the migration patterns of anti-third-party CTLs to that of naive host T cells, which showed that unlike naive host T cells that home efficiently to the LNs of BMT-recipient mice, veto CTLs are excluded from the LNs and tend to localize to peripheral sites. 58 To accommodate the need for veto cell LNs homing, a new type of host non-reactive veto cell with a central memory-like phenotype was successfully tested for induction of tolerance and engraftment of TDBMT.…”

Section: Combining Mismatched Tcd Megadose Bm With Adoptive Transfer mentioning

confidence: 95%

The role of donor-derived veto cells in nonmyeloablative haploidentical HSCT

Or-Geva

Reisner

2015

Bone Marrow Transplant

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Allogeneic HSCT offers a route for achieving immune tolerance via mixed chimerism and remains the sole curative option for many nonmalignant, autoimmune and metabolic diseases. Present-day improvements of nonmyeloablative protocols are increasing the safety of HSCT, thereby widening the target population and resurrecting the interest of HSCT application as a platform for tolerance induction in organ transplantation. Using high cell doses of T-cell-depleted (TCD) grafts has been shown to circumvent graft-vs-host disease, leaving graft rejection as the main hindrance due to the robust host immunity that remains after mild conditioning. In this review we highlight the advantages of utilizing unique non-alloreactive 'veto' cells, such as anti-third party central memory CD8 T cells (Tcm), to enable induction of mixed chimerism after megadose HSCT under nonmyeloablative conditioning. Co-administration of HSCT with veto Tcm allows for induction of mixed chimerism that was successfully translated into immune tolerance, as demonstrated by engraftment of donor-type skin grafts. These veto Tcm cells have been shown to specifically eradicate anti-donor host T cells, through lymph-node sequestration and deletion, thus sparing host immunity and circumventing the need for life-long immunosuppression. Hence, data indicate that this treatment modality of combined TCD HSCT and adoptive transfer of Tcm veto cells under nonmyeloablative conditions may serve as a valuable tool for treatment of patients with a wide array of disorders such as hemoglobinopathies, autoimmune diseases and as a prelude for organ tolerance.

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“…20,21 Thus, it is possible that anti-third-party CTLs fail to colocalize with the HTCs, preventing the veto CTLs from deleting antidonor HTCs at the lymph nodes (LNs). In turn, these antidonor cells are activated, lose their sensitivity to veto cellinduced apoptosis, 22 23,28,29 Similarly to "natural" Tcms, in vitro-generated Tcm-like cells are incapable of immediate cytotoxicity and display the typical Tcm migratory pattern. 27 Thus, our working hypothesis was that if it were possible to generate, ex vivo, anti-third-party CD8 ϩ T cells bearing a Tcm phenotype, such cells might be more effective in tolerance induction.…”

Section: Introductionmentioning

confidence: 99%

Induction of tolerance to bone marrow allografts by donor-derived host nonreactive ex vivo–induced central memory CD8 T cells

Ophir

Eidelstein

Afik

et al. 2010

Blood

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Enabling engraftment of allogeneic T celldepleted bone marrow (TDBM) under reduced-intensity conditioning represents a major challenge in bone marrow transplantation (BMT). Anti-third-party cytotoxic T lymphocytes (CTLs) were previously shown to be endowed with marked ability to delete host antidonor T cells in vitro, but were found to be less effective in vivo. This could result from diminished lymph node (LN) homing caused by the prolonged activation, which induces a CD44 ؉ CD62L ؊ effector phenotype, and thereby prevents effective colocalization with, and neutralization of, alloreactive host T cells (HTCs). In the present study, LN homing, determined by imaging, was enhanced upon culture conditions that favor the acquisition of CD44 ؉ CD62L ؉ central memory cell (Tcm) phenotype by anti-third-party CD8 ؉ cells. These Tcmlike cells displayed strong proliferation and prolonged persistence in BM transplant recipients. Importantly, adoptively transferred HTCs bearing a transgenic T-cell receptor (TCR) with antidonor specificity were efficiently deleted only by donor-type Tcms. All these attributes were found to be associated with improved efficacy in overcoming T cell-mediated rejection of TDBM, thereby enabling high survival rate and long-term donor chimerism, without causing graft-versus-host disease. In conclusion, anti-third-party Tcms, which home to recipient LNs and effectively delete antidonor T cells, could provide an effective and novel tool for overcoming rejection of BM allografts. IntroductionGraft-versus-host disease (GVHD) remains a major obstacle in bone marrow transplantation (BMT). BMT without GVHD can be achieved in severe combined immunodeficient patients by using T cell-depleted BM (TDBM) transplant or by using purified hematopoietic stem cells. 1 However, in leukemia patients, the benefit of GVHD prevention was offset by increased rejection rate of the TDBM transplant, 2,3 mediated by radiotherapy-and chemotherapy-resistant host-derived T cells (HTCs). 4,5 This barrier could be overcome by combining supralethal conditioning with functional inactivation of HTCs by "megadose" of purified CD34 stem cells. [6][7][8][9] Nevertheless, this strategy is hampered by considerable toxicity of the conditioning agents [10][11][12] and by increased risk of opportunistic infections due to slow immune reconstitution. Therefore, developing new strategies to achieve engraftment of TDBM transplant after reduced-intensity conditioning (RIC), which spares a substantial level of host immunity, is warranted.The finding that cells within the CD34 fraction are endowed with potent veto activity [13][14][15] has provided new insights into the mechanism by which CD34 megadose transplants can overcome the residual immunity in leukemia patients, after lethal conditioning. Veto activity was defined in 1980 by Miller 16 as the capacity to specifically suppress cytotoxic T lymphocyte precursor cells (CTLps), directed against antigens (Ags) of the veto cells themselves, but not against third-party Ags. Therefore, using veto c...

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Rapamycin Prolongs Susceptibility of Responding T Cells to Tolerance Induction by CD8+ Veto Cells

Cited by 13 publications

References 24 publications

Tolerance Induction in Presensitized Bone Marrow Recipients by Veto CTLs: Effective Deletion of Host Anti-Donor Memory Effector Cells

Tolerance Induction in Presensitized Bone Marrow Recipients by Veto CTLs: Effective Deletion of Host Anti-Donor Memory Effector Cells

The role of donor-derived veto cells in nonmyeloablative haploidentical HSCT

Induction of tolerance to bone marrow allografts by donor-derived host nonreactive ex vivo–induced central memory CD8 T cells

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