Rapamycin and IL-2 reduce lethal acute graft-versus-host disease associated with increased expansion of donor type CD4+CD25+Foxp3+ regulatory T cells

Shin, Ho-Jin; Baker, Jeanette; Leveson-Gower, Dennis B.; Smith, Aaron T.; Sega, Emanuela I.; Negrin, Robert S.

doi:10.1182/blood-2010-10-313684

Cited by 137 publications

(119 citation statements)

References 52 publications

(56 reference statements)

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“…21 In our study, we treated donors with aDR3 and performed bone marrow transplantation (BMT) in an MHC I/II-mismatched murine model. 17,22 We found that donor Tregs markedly expanded, resulting in significant reduction of acute GVHD without impairment of GVT effects.…”

Section: Cd25mentioning

confidence: 87%

“…15,16 We previously reported that the combined administration of rapamycin and IL-2 expanded donor Tregs and reduced acute GVHD in a murine model. 17 However, these agents could work nonspecifically and might adversely affect other cell populations. Therefore, alternative strategies for the activation and expansion of Tregs are needed.…”

Section: Cd25mentioning

confidence: 99%

“…17,22 Briefly, BALB/c recipient mice were irradiated with 850 cGy in 2 split doses on day 0. T cell-depleted bone marrow (TCD-BM) cells were isolated from wild-type nontreated C57BL/6 mice, whereas donor T cells were obtained from mAb-treated (aDR3 or isotypemAb) C57BL/6 donor mice.…”

mentioning

confidence: 99%

“…28 To evaluate GVT effects, 2 3 10 4 luc Cells were harvested from MLR plates after culture for 96 hours or were reisolated from BMT recipients on days 3, 7, 14, and 28. 17 For intracellular cytokine staining, cells were stimulated with Cell Stimulation Cocktail (eBioscience) for 5 hours, fixed with FoxP3 Fixation/Permeabilization buffer (eBioscience), and stained for intracellular molecules. For BrdU staining, the recipient mice were injected intraperitoneally with 1 mg of BrdU at 1 and 2 days before analysis.…”

mentioning

confidence: 99%

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Treatment with agonistic DR3 antibody results in expansion of donor Tregs and reduced graft-versus-host disease

Kim

Nishikii

Baker

et al. 2015

Blood

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Key Points• Donor treatment with agonistic DR3 antibody induces selective expansion of Tregs and reduced activation of conventional T cells.• T cells from DR3 antibodytreated donors result in reduced acute GVHD and preserved GVT effects. numbers of Tregs and were less proliferative to allogeneic stimuli. In vivo GVHD studies confirmed that Tregs from aDR3-treated donors expanded robustly and higher frequencies of Tregs within donor CD4 1 T cells were maintained, resulting in improved survival. Conventional T cells derived from aDR3-treated donors showed reduced activation and proliferation. Serum levels of proinflammatory cytokines (IFNg, IL-1b, and TNFa) and infiltration of donor T cells into GVHD target tissues (gastrointestinal tract and liver) were decreased. T cells from aDR3-treated donors retained graft-vs-tumor (GVT) effects. In conclusion, a single dose of aDR3 alleviates acute GVHD while preserving GVT effects by selectively expanding and maintaining donor Tregs. This novel strategy will facilitate the clinical application of Treg-based therapies. (Blood. 2015; 126(4):546-557)

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Section: Cd25mentioning

confidence: 87%

Section: Cd25mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Treatment with agonistic DR3 antibody results in expansion of donor Tregs and reduced graft-versus-host disease

Kim

Nishikii

Baker

et al. 2015

Blood

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“…It is recommended to monitor patients for renal function, hyperlipidemia, myelosuppression particularly thrombocytopenia and thrombotic microangiopathy while on treatment with sirolimus. It was shown that sirolimus preserves Tregs while CIs suppress Tregs [144,145]. For that reason sirolimus is increasingly used for the treatment of CI-refractory cGVHD, by tapering off CIs while gradually increasing the dose of sirolimus to achieve the therapeutic levels.…”

Section: Sirolimusmentioning

confidence: 99%

State-of-the-art acute and chronic GVHD treatment

Jamil

Mineishi

2015

Int J Hematol

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owing to the advancement in reduced intensity conditioning (RIC) and in patients without HLA-matched donors due to the use of cord blood and haploidentical HSCT [4][5][6]. Although marked improvement has been made in supportive care, immunosuppressive therapy and DNA-based Human Leukocyte Antigen (HLA) typing, graft vs host disease (GVHD) remains a major cause of morbidity and non-relapse mortality among allogeneic HSCT recipients. It was first described by Billingham in 1966 as a syndrome where immunocompetent T cells from the donor recognize and damage the host tissue in an immunocompromised recipient. It presents with heterogeneous symptoms involving multiple organ systems including gastrointestinal tract, skin, mucosa, liver and lungs [7]. In the past clinical features occurring within 100 days after HSCT was called acute GVHD (aGVHD) and those happening after 100 days were labeled chronic GVHD (cGVHD) [8,9]. This definition was rather unsatisfactory thus National Institute of Health (NIH) consensus criteria were developed and have been revised. The criteria have added new categories such as late-onset aGVHD (acute GVHD occurring after 100 days) and overlap syndrome which includes features of both acute and chronic GVHD to the classification, and also have introduced new definitions for organ system involvement [10][11][12]. The categorization of acute vs chronic GVHD is based on the combination of clinical symptoms rather than the time of onset. Depending upon a number of variables associated with patients, donors, and types of transplant, the incidence of aGVHD varies with incidence of grade II-IV GVHD at 40 % in matched related donor (MRD) transplant to 50 % in MUD transplant. The main risk factors for aGVHD include degree of HLA mismatch, age of the patient, previous all immunization of the donor and the kind of GVHD prophylaxis used. About 30-70 % of allogeneic HSCT recipients alive after 100 days will Abstract Graft-versus-host disease (GVHD) remains as the major obstacle for successful hematopoietic stem cell transplant (HSCT). Roughly half of the patients undergoing HSCT develop GVHD which requires treatment, and above 10 % of the patient may die because of it. However, GVHD presents with anti-tumor activity, called graft-versus-tumor (GVT) effect, and it carries significant anti-tumor activity, thus suppressing GVHD completely may increase the relapse of original disease. Thus, it is important to control GVHD to the appropriate level.

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Immune Regulation in Hematopoietic Cell Transplantation

Negrin¹,

Ritz²

2015

Thomas’ Hematopoietic Cell Transplantation

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Rapamycin and IL-2 reduce lethal acute graft-versus-host disease associated with increased expansion of donor type CD4+CD25+Foxp3+ regulatory T cells

Cited by 137 publications

References 52 publications

Treatment with agonistic DR3 antibody results in expansion of donor Tregs and reduced graft-versus-host disease

Treatment with agonistic DR3 antibody results in expansion of donor Tregs and reduced graft-versus-host disease

State-of-the-art acute and chronic GVHD treatment

Immune Regulation in Hematopoietic Cell Transplantation

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