Superior immune reconstitution using Treg-expanded donor cells versus PTCy treatment in preclinical HSCT models

Wolf, Dietlinde; Bader, Cameron S.; Barreras, Henry; Copsel, Sabrina N.; Pfeiffer, Brent J.; Lightbourn, Casey O.; Altman, Norman H.; Komanduri, Krishna V.; Levy, Robert B.

doi:10.1172/jci.insight.121717

Cited by 17 publications

(18 citation statements)

References 60 publications

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“…Prior studies using cyclophosphamide following CT did not observe prolonged allograft survival ( 8 , 9 ). In contrast, the findings here demonstrated that PTCy usage can prolong survival of these CT when administered at selective times distinct from optimal Cy kinetics post-HSCT ( 1 , 31 , 42 ). Results also identified the presence of Treg cells following PTCy treatment in both the pre-clinical liquid and solid tissue graft models.…”

Section: Discussioncontrasting

confidence: 75%

“…Compared to untreated (“control”) recipients, treatment with 70 mg/kg at D6, 7 ± 9 significantly prolonged CT whereas earlier PTCy, i.e., at D.5 + 6 did not. Next, transplant experiments compared the administration of 70 and 90 −50 mg/kg, the latter which effectively inhibited B6BALB/c hematopoietic stem cell grafts ( Figure 1 ) ( 31 ). Results from BALB/c recipients receiving 70 mg/kg on D6 + 7 post-transplant of B6 CT allografts indicated that this dose was superior to 50 mg/kg for prolonging these CT allografts and 90 mg/kg was found to have the most pronounced effect on prolonging graft survival ( Figure 3 ).…”

Section: Resultsmentioning

confidence: 99%

“…MHC-mismatched pre-clinical and clinical aHSCT (31)(32)(33). To more precisely address the dose of PTCy which can ameliorate pre-clinical GVHD in this model, transplants were performed across a complete MHC disparity and varying doses of PTCy were administered on days 3 + 4 to BALB/c (H2 d ) recipients following transplant with B6 (H2 b ) donor cells (Figure 1).…”

Section: Cyclophosphamide Treatment Post-hematopoietic Stem Cell Tranmentioning

confidence: 99%

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Use of Post-transplant Cyclophosphamide Treatment to Build a Tolerance Platform to Prevent Liquid and Solid Organ Allograft Rejection

et al. 2021

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Corneal transplantation (CT) is the most frequent type of solid organ transplant (SOT) performed worldwide. Unfortunately, immunological rejection is the primary cause of graft failure for CT and therefore advances in immune regulation to induce tolerance remains an unmet medical need. Recently, our work and others in pre-clinical studies found that cyclophosphamide (Cy) administered after (“post-transplant,” PTCy) hematopoietic stem cell transplantation (HSCT), i.e., liquid transplants is effective for graft vs. host disease prophylaxis and enhances overall survival. Importantly, within the past 10 years, PTCy has been widely adopted for clinical HSCT and the results at many centers have been extremely encouraging. The present studies found that Cy can be effectively employed to prolong the survival of SOT, specifically mouse corneal allografts. The results demonstrated that the timing of PTCy administration is critical for these CT and distinct from the kinetics employed following allogeneic HSCT. PTCy was observed to interfere with neovascularization, a process critically associated with immune rejection of corneal tissue that ensues following the loss of ocular “immune privilege.” PTCy has the potential to delete or directly suppress allo-reactive T cells and treatment here was shown to diminish T cell rejection responses. These PTCy doses were observed to spare significant levels of CD4+ FoxP3+ (Tregs) which were found to be functional and could readily receive stimulating signals leading to their in vivo expansion via TNFRSF25 and CD25 agonists. In total, we posit future studies can take advantage of Cy based platforms to generate combinatorial strategies for long-term tolerance induction.

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Section: Discussioncontrasting

confidence: 75%

Section: Resultsmentioning

confidence: 99%

Section: Cyclophosphamide Treatment Post-hematopoietic Stem Cell Tranmentioning

confidence: 99%

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Use of Post-transplant Cyclophosphamide Treatment to Build a Tolerance Platform to Prevent Liquid and Solid Organ Allograft Rejection

et al. 2021

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“…We have previously reported that Tregs can be markedly expanded and selectively activated with increased functional capacity by targeting two receptors, i.e., TNFRSF25 and CD25 with TL1A-Ig and low dose IL-2, respectively (7, 8). Additionally, expanded Treg therapy was shown to be as effective as post-transplant cyclophosphamide for GVHD prophylaxis but the former promoted more rapid thymic reconstitution providing earlier recovery of recipient immune function (37). Acute GVHD occurs when donor T cells are primed by recipient antigens subsequently eliciting a rapid inflammatory response (“cytokine storm”) in the host.…”

Section: Discussionmentioning

confidence: 99%

BET Bromodomain Inhibitors Which Permit Treg Function Enable a Combinatorial Strategy to Suppress GVHD in Pre-clinical Allogeneic HSCT

et al. 2019

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A recent approach for limiting production of pro-inflammatory cytokines has been to target bromodomain and extra-terminal (BET) proteins. These epigenetic readers of histone acetylation regulate transcription of genes involved in inflammation, cardiovascular disease, and cancer. Development of BET inhibitors (BETi) has generated enormous interest for their therapeutic potential. Because inflammatory signals and donor T cells promote graft-versus-host disease (GVHD), regulating both pathways could be effective to abrogate this disorder. The objective of the present study was to identify a BETi which did not interfere in vivo with CD4+FoxP3+ regulatory T cell (Treg) expansion and function to utilize together with Tregs following allogeneic hematopoietic stem cell transplantation (aHSCT) to ameliorate GVHD. We have reported that Tregs can be markedly expanded and selectively activated with increased functional capacity by targeting TNFRSF25 and CD25 with TL1A-Ig and low dose IL-2, respectively. Here, mice were treated over 7 days (TL1A-Ig + IL-2) together with BETi. We found that the BETi EP11313 did not decrease frequency/numbers or phenotype of expanded Tregs as well as effector molecules, such as IL-10 and TGF-β. However, BETi JQ1 interfered with Treg expansion and altered subset distribution and phenotype. Notably, in Treg expanded mice, EP11313 diminished tnfa and ifng but not il-2 RNA levels. Remarkably, Treg pSTAT5 expression was not affected by EP11313 supporting the notion that Treg IL-2 signaling remained intact. MHC-mismatched aHSCT (B6 → BALB/c) was performed using in vivo expanded donor Tregs with or without EP11313 short-term treatment in the recipient. Early post-transplant, improvement in the splenic and LN CD4/CD8 ratio along with fewer effector cells and high Treg levels in aHSCT recipients treated with expanded Tregs + EP11313 was detected. Interestingly, this group exhibited a significant diminution of GVHD clinical score with less skin and ocular involvement. Finally, using low numbers of highly purified expanded Tregs, improved clinical GVHD scores were observed in EP11313 treated recipients. In total, we conclude that use of this novel combinatorial strategy can suppress pre-clinical GVHD and posit, in vivo EP11313 treatment might be useful combined with Treg expansion therapy for treatment of diseases involving inflammatory responses.

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“…132 Furthermore, TL1A-Ig/IL-2 expanded Treg therapy was shown to be as effective as post-transplant cyclophosphamide for GvHD prophylaxis while more rapid thymic reconstitution providing earlier recovery of recipient immune function. 136 GvHD is promoted by alloreactive donor T cells and inflammation; therefore, we proposed to regulate both pathways. Donor Treg expansion was combined with EP11313 (a bromodomain and extra-terminal bromodomain inhibitor, BETi) using short-term treatment in the recipient in a fully MHC-mismatched aHSCT.…”

Section: Targeting Cell Surface Receptors For In Vivo Treg Expansionmentioning

confidence: 99%

The promise of CD4⁺FoxP3⁺ regulatory T-cell manipulation in vivo: applications for allogeneic hematopoietic stem cell transplantation

Copsel¹,

Wolf

Komanduri

et al. 2019

Haematologica

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CD4 + FoxP3 + regulatory T cells (Tregs) are a non-redundant population critical for the maintenance of self-tolerance. Over the past decade, the use of these cells for therapeutic purposes in transplantation and autoimmune disease has emerged based on their capacity to inhibit immune activation. Basic science discoveries have led to identifying key receptors on Tregs that can regulate their proliferation and function. Notably, the understanding that IL-2 signaling is crucial for Treg homeostasis promoted the hypothesis that in vivo IL-2 treatment could provide a strategy to control the compartment. The use of low-dose IL-2 in vivo was shown to selectively expand Tregs versus other immune cells. Interestingly, a number of other Treg cell surface proteins, including CD28, CD45, IL-33R and TNFRSF members, have been identified which can also induce activation and proliferation of this population. Pre-clinical studies have exploited these observations to prevent and treat mice developing autoimmune diseases and graft- versus -host disease post-allogeneic hematopoietic stem cell transplantation. These findings support the development of translational strategies to expand Tregs in patients. Excitingly, the use of low-dose IL-2 for patients suffering from graft- versus -host disease and autoimmune disease has demonstrated increased Treg levels together with beneficial outcomes. To date, promising pre-clinical and clinical studies have directly targeted Tregs and clearly established the ability to increase their levels and augment their function in vivo . Here we review the evolving field of in vivo Treg manipulation and its application to allogeneic hematopoietic stem cell transplantation.

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Superior immune reconstitution using Treg-expanded donor cells versus PTCy treatment in preclinical HSCT models

Cited by 17 publications

References 60 publications

Use of Post-transplant Cyclophosphamide Treatment to Build a Tolerance Platform to Prevent Liquid and Solid Organ Allograft Rejection

Use of Post-transplant Cyclophosphamide Treatment to Build a Tolerance Platform to Prevent Liquid and Solid Organ Allograft Rejection

BET Bromodomain Inhibitors Which Permit Treg Function Enable a Combinatorial Strategy to Suppress GVHD in Pre-clinical Allogeneic HSCT

The promise of CD4⁺FoxP3⁺ regulatory T-cell manipulation in vivo: applications for allogeneic hematopoietic stem cell transplantation

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Superior immune reconstitution using Treg-expanded donor cells versus PTCy treatment in preclinical HSCT models

Cited by 17 publications

References 60 publications

Use of Post-transplant Cyclophosphamide Treatment to Build a Tolerance Platform to Prevent Liquid and Solid Organ Allograft Rejection

Use of Post-transplant Cyclophosphamide Treatment to Build a Tolerance Platform to Prevent Liquid and Solid Organ Allograft Rejection

BET Bromodomain Inhibitors Which Permit Treg Function Enable a Combinatorial Strategy to Suppress GVHD in Pre-clinical Allogeneic HSCT

The promise of CD4+FoxP3+ regulatory T-cell manipulation in vivo: applications for allogeneic hematopoietic stem cell transplantation

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Product

Resources

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The promise of CD4⁺FoxP3⁺ regulatory T-cell manipulation in vivo: applications for allogeneic hematopoietic stem cell transplantation