Impact of immunosuppressive drugs on the therapeutic efficacy of ex vivo expanded human regulatory T cells

Scottà, Cristiano; Fanelli, Giorgia; Hoong, Sec Julie; Romano, Marco; Lamperti, Estefania Nova; Sukthankar, Mitalee; Guggino, Giuliana; Fazekasova, Henrieta; Ratnasothy, Kulachelvy; Becker, Pablo D.; Afzali, Behdad; Lechler, Robert I.; Lombardi, Giovanna

doi:10.3324/haematol.2015.128934

Cited by 65 publications

(43 citation statements)

References 50 publications

(69 reference statements)

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“…Within a clinical context it is important to consider the effects of immunosuppressive drugs on Tregs. Treatment with calcineurin inhibitors decreases Treg viability and proliferation (13). The effects of mycophenolic acid on Tregs appear to be more variable (14)(15)(16) whereas glucocorticoids appear not to affect Tregs, although one study has described steroid-related IL-2dependent expansion of Tregs (17).…”

Section: Expansion Of Natural Tregsmentioning

confidence: 99%

Regulatory T Cells and Kidney Transplantation

Martín-Moreno

Tripathi

Chandraker

2018

CJASN

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The ability of the immune system to differentiate self from nonself is critical in determining the immune response to antigens expressed on transplanted tissue. Even with conventional immunosuppression, acceptance of the allograft is an active process often determined by the presence of regulatory T cells (Tregs). Tregs classically are CD4 cells that constitutively express high levels of the IL-2 receptor chain CD25, along with the transcription factor Foxp3. The use of Tregs in the field of solid organ transplantation is related specifically to the objective of achieving tolerance, with the goal of reducing or eliminating immunosuppressive drugs as well as maintaining tissue repair and managing acute rejection. A key issue in clinical use of Tregs is how to effectively expand the number of Tregs, either through increasing numbers of endogenous Tregs or by the direct infusion of exogenously expanded Tregs. In order to realize the benefits of Treg therapy in solid organ transplantation, a number of outstanding challenges need to be overcome, including assuring an effective expansion of Tregs, improving long-term Treg stability and reduction of risk-related to off-target, nonspecific, immunosuppressive effects related specially to cancer.

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Section: Expansion Of Natural Tregsmentioning

confidence: 99%

Regulatory T Cells and Kidney Transplantation

Martín-Moreno

Tripathi

Chandraker

2018

CJASN

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“…rapamycin and everolimus) bind to FKBP12 (FK506 binding protein 12) and suppresses mTORc1. Interestingly, rapamycin was shown to maintain or to promote human Treg expansion and function in vitro and in vivo . In addition, rapamycin synergized with ex vivo expanded human Tregs in inhibiting vascular allograft rejection in a humanized transplant model of arteriosclerosis .…”

Section: Tregs and Immunosuppressive Drugsmentioning

confidence: 99%

“…Contradictory in vitro effects of MMF on Tregs have been reported. On the one hand, MMF has been shown to promote induction of Tregs from Tconv , while other reports suggest that MMF has a dose‐dependent deleterious effect on human Tregs by decreasing their viability and proliferative capacity . To date, the effects of MMF or azathioprine (a purine analog) on Tregs in transplant patients remain unclear.…”

Section: Tregs and Immunosuppressive Drugsmentioning

confidence: 99%

Treg-Centric View of Immunosuppressive Drugs in Transplantation: A Balancing Act

Camirand

Riella

2017

American Journal of Transplantation

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Regulatory CD4+ Foxp3+ T cells (Tregs) are critical in controlling immunity and tolerance. Thus, preserving Treg numbers and function in transplanted patients is essential for the successful minimization of maintenance immunosuppression. Multiple cellular signals control the development, differentiation, and function of Tregs. Many of these signals are shared with conventional Foxp3 T cells (Tconv) and are targeted by immunosuppressive drugs, negatively affecting both Tregs and Tconv. Because intracellular signals vary in optimal intensity in different T cell subsets, improved specificity in immunosuppressive regimens must occur to benefit long-term transplant outcomes. In this regard, recent advances are gradually uncovering differences in the signals required in Tregs and Tconv biology, opening the door to new potential therapeutic approaches to either enhance or spare Tregs. In this review, we will explain the prominent cell signaling pathways critical for Treg maintenance and function, while reporting the effects of immunosuppressive drugs targeting these signaling pathways in clinical transplantation settings.

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“…This could affect regulatory cells survival and functions. Indeed, tacrolimus, mycophenolate mofetil (MMF), and methylprednisolone do not affect phenotype, function, or stability of Tregs, but reduce their proliferative capacity, whereas rapamycin did not [288][289][290]. Moreover, rapamycin is sometimes used to maintain regulatory properties of Tregs during expansion culture and also to convert conventional CD4 + T cells into Tregs ex vivo [291].…”

Section: From Patients Observation To Actionmentioning

confidence: 99%

Tolerance in Organ Transplantation

Boucault¹,

Bézie²,

Ossart³

et al. 2016

Frontiers in Transplantology

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Transplantation is often the best option to treat organ end stage failure. Transplanted patients need to take long-term immunosuppressive drugs to inhibit rejection and maintain their graft. "ut those therapies have numerous important side effects such as cancer induction and opportunistic infections. Thus, the development of novel therapies to induce specific rather than general immunosuppression and therefore, tipping the balance between effector and regulatory functions to inhibit transplant rejection is a major goal in the field. One major approach is the blockade of costimulatory signals to abort effector T-cell activation following TCR engagement and to promote regulatory T cells. Here we summarized the research to date that details immune mechanisms involved in tolerance in organ transplantation and strategies toward tolerance.

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Impact of immunosuppressive drugs on the therapeutic efficacy of ex vivo expanded human regulatory T cells

Cited by 65 publications

References 50 publications

Regulatory T Cells and Kidney Transplantation

Regulatory T Cells and Kidney Transplantation

Treg-Centric View of Immunosuppressive Drugs in Transplantation: A Balancing Act

Tolerance in Organ Transplantation

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