Calcineurin Inhibitors, but not Rapamycin, Reduce Percentages of CD4+CD25+FOXP3+ Regulatory T Cells in Renal Transplant Recipients

Segundo, David San; Ruiz, J.C.; Izquierdo, M J; Fernández‐Fresnedo, Gema; Gómez-Alamillo, C.; Merino, Ramón; Benito, M. Isabel; Cacho, Eva; Rodrigo, Emilio; Palomar, Rosa; López-Hoyos, Marcos; Arias, Manuel

doi:10.1097/01.tp.0000229473.95202.50

Cited by 220 publications

(165 citation statements)

References 40 publications

(49 reference statements)

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“…[1][2][3] The incidence of chronic GVHD with the use of a calcineurin inhibitor plus methotrexate (MTX) after peripheral blood stem cell transplantation is in the range of 40-70%, and more than one-third of the patients require immunosuppression for up to four years after transplant. 3,4 These data suggest that immune tolerance is not obtained in the long term in an important subset of patients and, in fact, are consistent with those from in vitro studies showing that calcineurin inhibitors block the expansion and function of regulatory T cells (Treg) [5][6][7][8][9][10] which are essential for the generation of a tolerogeneic immune response. The use of in vivo or in vitro T-cell depletion significantly reduces the risk of GVHD but has not led to an improved survival, due to an increase in the incidence of severe infections and relapses.…”

Section: Introductionsupporting

confidence: 65%

“…Also, signs of GVHD significantly improved in the group of mice receiving both drugs as compared to each drug alone ( Figure 5B). In order to better determine the effect of the combination of sirolimus and bortezomib on survival, a severe GVHD model was established using 10×10 6 splenocytes. Survival was again significantly better in the group of mice receiving both drugs, thus confirming in vivo the results previously shown in vitro ( Figure 5A).…”

Section: In Vivo Studies: Sirolimus Plus Bortezomib Prevents Gvhdmentioning

confidence: 99%

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The novel combination of sirolimus and bortezomib prevents graft-versus-host disease but maintains the graft-versus-leukemia effect after allogeneic transplantation

et al. 2012

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The online version of this article has a Supplementary Appendix. BackgroundWe have previously shown that bortezomib induces a depletion of alloreactive T cells and allows the expansion of T cells with suppressive properties. In the current study, we analyzed the potential synergistic effect of bortezomib in conjunction with sirolimus in order to reducegraft-versus-host disease without hampering graft-versus-leukemia effect in the allogeneic transplant setting. Design and MethodsWe evaluated the effect of sirolimus, bortezomib or the combination of both in the proliferation and activation of in vitro stimulated T lymphocytes. Pathways involved in this synergy were also analyzed using Western blot assays. Finally, BALB/c mice receiving C57BL/6 allogeneic donor bone marrow with splenocytes were used to measure in vivo the effect of this novel combination on the risk of graft-versus-host disease. ResultsThe combination of both drugs synergistically inhibited both activation and proliferation of stimulated T cells. Also, the production of Th1 cytokines (IFN γ, IL-2 and TNF) was significantly inhibited. This effect was due, at least in part, to the inhibition of Erk and Akt phosphorylation. In vivo, the combination reduced the risk of graft-versus-host disease without hampering graft-versus-leukemia effect, as shown in mice receiving graft-versus-host disease prophylaxis with sirolimus plus bortezomib being infused with tumor WEHI cells plus C57BL/6 donor BM and splenocytes. ConclusionsThe current study reveals a synergistic effect of the combination sirolimus and bortezomib to prevent graft-versus-host disease while maintaining the graft-versus-leukemia effect.Key words: allogeneic transplant, sirolimus, bortezomib, graft-versus-host, graft-versusleukemia. Haematologica 2012;97(9):1329-1337. doi:10.3324/haematol.2011 This is an open-access paper. © F e r r a t a S t o r t i F o u n d a t i o n © F e r r a t a S t o r t i F o u n d a t i o n Citation: Caballero-Velázquez T, Sánchez-Abarca LI, Gutierrez-Cosio S, Blanco B, Calderon C, Herrero C, Carrancio S, Serrano C, del Cañizo C, San Miguel JF, and Pérez-Simón JA. The novel combination of sirolimus and bortezomib prevents graft-versus-host disease but maintains the graftversus-leukemia effect after allogeneic transplantation. The novel combination of sirolimus and bortezomib prevents graft-versus-host disease but maintains the graft-versus-leukemia effect after allogeneic transplantation

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Section: Introductionsupporting

confidence: 65%

Section: In Vivo Studies: Sirolimus Plus Bortezomib Prevents Gvhdmentioning

confidence: 99%

The novel combination of sirolimus and bortezomib prevents graft-versus-host disease but maintains the graft-versus-leukemia effect after allogeneic transplantation

et al. 2012

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“…59 On the other hand, MMF and lowdose tacrolimus had an induction of CD4+CD25+FOXP3+ Tregs as showed in kidney transplanted recipients treated with these drugs that permit Tregs expansion in the periphery and accumulation in the allograft and the maintenance of their suppressive function which was confirmed by in vitro analysis of these cells. 60 Other studies showed that MMF has no effect on Tregs numbers and function but may facilitate the induction of a more tolerogenic environment.…”

Section: Strategies To Tailor Immunosuppressive Therapy To Ensure Thementioning

confidence: 74%

After Moving of Regulatory T-Cell Therapy to the Clinic: Will We Need a New Tregs Source?

El-Badry

Noreldin

Hassanein

2017

HTIJ

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“…This was not observed in mice that only received SIR but not donor WBM. As SIR increases Treg survival and function in mice (35,40) and humans (41,42), our data suggest that Tregs are induced in the presence of alloantigen and preferentially survive under the influence of SIR (35). This increase may be important for complete tolerance, since partial Treg depletion using PC61 antibody treatment impacted upon the extent of graft acceptance.…”

Section: Discussionmentioning

confidence: 86%

Establishment of Transplantation Tolerance via Minimal Conditioning in Aged Recipients

Morison

Homann

Hammett

et al. 2014

American Journal of Transplantation

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y Co-senior authors.Mixed hematopoietic chimerism is a powerful means of generating donor-specific tolerance, allowing longterm graft acceptance without lifelong dependence on immunosuppressive drugs. To avoid the need for whole body irradiation and associated side effects, we utilized a radiation-free minimal conditioning regime to induce long-term tolerance across major histocompatibility barriers. We found that low-dose busulfan, in combination with host T cell depletion and short-term sirolimus-based immunosuppression, facilitated efficient donor engraftment. Tolerance was achieved when mice were transplanted with whole or T cell-depleted bone marrow, or purified progenitor cells. Tolerance induction was associated with an expansion in regulatory T cells and was not abrogated in the absence of a thymus, suggesting a dominant or compensatory peripheral mode of tolerance. Importantly, we were able to generate durable chimerism and tolerance to donor skin grafts in both young and aged mice, despite age-related thymic atrophy and immune senescence. Clinically, this is especially relevant as the majority of transplant recipients are older patients whose immune recovery might be dangerously slow and would benefit from radiation-free minimal conditioning regimes that allow efficient donor engraftment without fully ablating the recipient immune system.

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Calcineurin Inhibitors, but not Rapamycin, Reduce Percentages of CD4+CD25+FOXP3+ Regulatory T Cells in Renal Transplant Recipients

Cited by 220 publications

References 40 publications

The novel combination of sirolimus and bortezomib prevents graft-versus-host disease but maintains the graft-versus-leukemia effect after allogeneic transplantation

The novel combination of sirolimus and bortezomib prevents graft-versus-host disease but maintains the graft-versus-leukemia effect after allogeneic transplantation

After Moving of Regulatory T-Cell Therapy to the Clinic: Will We Need a New Tregs Source?

Establishment of Transplantation Tolerance via Minimal Conditioning in Aged Recipients

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