Ex Vivo Costimulatory Blockade to Generate Regulatory T Cells From Patients Awaiting Kidney Transplantation

Guinan, Eva C.; Cole, Gerald A.; Wylie, William. H.; Kelner, R. H.; Janec, K. J.; Yuan, Huaiping; Oppatt, J.; Brennan, Lisa; Turka, Laurence A.; Markmann, James F.

doi:10.1111/ajt.13725

Cited by 40 publications

(44 citation statements)

References 29 publications

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“…Here, we have expanded polyclonal Tregs and tested their safety after reinfusion in kidney transplant recipients on tacrolimus, mycophenolate mofetil and corticosteroids. While Tregs have been previously isolated from uremic patients , this is the first report showing that isolation and expansion of Tregs is not only possible from kidney transplant recipients on immunosuppression but also feasible in sufficient numbers for in vivo therapy. The Treg infusions were well tolerated without cytokine release, infusion reactions, or infectious complications.…”

Section: Discussionmentioning

confidence: 99%

Polyclonal Regulatory T Cell Therapy for Control of Inflammation in Kidney Transplants

Chandran

Tang

Sarwal

et al. 2017

American Journal of Transplantation

193

169

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Early subclinical inflammation in kidney transplants is associated with later graft fibrosis and dysfunction. Regulatory T cells (Tregs) can reverse established inflammation in animal models. We conducted a pilot safety and feasibility trial of autologous Treg cell therapy in three kidney transplant recipients with subclinical inflammation noted on 6-month surveillance biopsies. Tregs were purified from peripheral blood and polyclonally expanded ex vivo using medium containing deuterated glucose to label the cells. All patients received a single infusion of ~320 × 106 (319, 321 and 363.8 × 106) expanded Tregs. Persistence of the infused Tregs was tracked. Graft inflammation was monitored with follow-up biopsies and urinary biomarkers. Nearly 1 × 109 (0.932, 0.956, 1.565 × 109) Tregs were successfully manufactured for each patient. There were no infusion reactions or serious therapy-related adverse events. The infused cells demonstrated patterns of persistence and stability similar to those observed in non-immunosuppressed subjects receiving the same dose of Tregs. Isolation and expansion of Tregs is feasible in kidney transplant patients on immunosuppression. Infusion of these cells was safe and well tolerated. Future trials will test the efficacy of polyclonal and donor alloantigen-reactive Tregs for the treatment of inflammation in kidney transplants.

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Section: Discussionmentioning

confidence: 99%

Polyclonal Regulatory T Cell Therapy for Control of Inflammation in Kidney Transplants

Chandran

Tang

Sarwal

et al. 2017

American Journal of Transplantation

193

169

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“…We showed that regulatory T cells may be partially spared of the suppressive effects of PI3K inhibitors compared with CD4 + lymphocytes. Therefore, PI3K and MEK inhibitors might be useful primarily, or as adjunct to costimulatory blockade in ex vivo Treg manufacturing to enhance Treg yields from a mixed starting population. Moreover, they may preferentially target Teff responses in vivo , while relatively preserving Treg activation and function.…”

Section: Discussionmentioning

confidence: 99%

Selective Sparing of Human Tregs by Pharmacologic Inhibitors of the Phosphatidylinositol 3-Kinase and MEK Pathways

Zwang

Zhang

Germana

et al. 2016

American Journal of Transplantation

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Phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase/extracellular signal-regulated (MEK) signaling are central to the survival and proliferation of many cell types. Multiple lines of investigation in murine models have shown that control of the PI3K pathway is particularly important for regulatory T cell (Treg) stability and function. PI3K and MEK inhibitors are being introduced into the clinic, and we hypothesized that pharmacologic inhibition of PI3K, and possibly MEK, in mixed cultures of human mononuclear cells would preferentially affect CD4+ and CD8+ lymphocytes compared with Tregs. We tested this hypothesis using four readouts: proliferation, activation, functional suppression, and signaling. Results showed that Tregs were less susceptible to inhibition by both δ and α isoform–specific PI3K inhibitors and by an MEK inhibitor compared with their conventional CD4+ and CD8+ counterparts. These studies suggest less functional reliance on PI3K and MEK signaling in Tregs compared with conventional CD4+ and CD8+ lymphocytes. Therefore, the PI3K and MEK pathways are attractive pharmacologic targets for transplantation and treatment of autoimmunity.

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“…Interestingly, a recent study reported the generation of Tregs from the PBMCs of uremic recipients and of healthy donors using ex vivo co-stimulation with belatacept (a second-generation CTLA4Ig) during a mixed lymphocyte reaction21. It appears to be clinically feasible to use Treg to decrease alloresponsiveness and to limit the need for pharmacologic immunosuppressants during kidney transplantation.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of toll-like receptor 4 signaling pathways ameliorate bone graft rejection in a mouse model of allograft transplantation

Hsieh

Shen

et al. 2017

Sci Rep

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Non-union occurring in structural bone grafting is a major problem in allograft transplantation because of impaired interaction between the host and graft tissue. Activated toll-like receptor (TLR) induces inflammatory cytokines and chemokines and triggers cell-mediated immune responses. The TLR-mediated signal pathway is important for mediating allograft rejection. We evaluated the effects of local knockdown of the TLR4 signaling pathway in a mouse segmental femoral graft model. Allografts were coated with freeze-dried lentiviral vectors that encoded TLR4 and myeloid differentiation primary response gene 88 (MyD88) short-hairpin RNA (shRNA), which were individually transplanted into the mice. They were assessed morphologically, radiographically, and histologically for tissue remodeling. Union occurred in autografted but not in allografted mice at the graft and host junctions after 4 weeks. TLR4 and MyD88 expression was up-regulated in allografted mice. TLR4 and MyD88 shRNAs inhibited TLR4 and MyD88 expression, which led to better union in the grafted sites. More regulatory T-cells in the draining lymph nodes suggested inflammation suppression. Local inhibition of TLR4 and MyD88 might reduce immune responses and ameliorate allograft rejection.

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Ex Vivo Costimulatory Blockade to Generate Regulatory T Cells From Patients Awaiting Kidney Transplantation

Cited by 40 publications

References 29 publications

Polyclonal Regulatory T Cell Therapy for Control of Inflammation in Kidney Transplants

Polyclonal Regulatory T Cell Therapy for Control of Inflammation in Kidney Transplants

Selective Sparing of Human Tregs by Pharmacologic Inhibitors of the Phosphatidylinositol 3-Kinase and MEK Pathways

Knockdown of toll-like receptor 4 signaling pathways ameliorate bone graft rejection in a mouse model of allograft transplantation

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