Preoperative application of combination of portal venous injection of donor spleen cells and intraperitoneal injection of rapamycin prolongs the survival of cardiac allografts in mice

Gong, Wenlin; Sha, Chuang; Du, Gang; Zhang, Shan; Qi, Zhongquan; Zhou, Sufang; Yang, Nuo; Zhao, Yongxiang

doi:10.1016/j.apjtm.2017.05.004

Cited by 3 publications

(2 citation statements)

References 21 publications

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“…50 Administration of rapamycin has been shown by many investigators to promote the expansion of CD4 + Treg but has been shown to be unable to inhibit the replication of memory T cells, even when combined with donor-specific transfusion (DST) in mice. 51 However, mammalian target of rapamycin (mTOR) inhibition via everolimus, in the context of costimulation blockade-resistant rejection that was nonresponsive to corticosteroids and ATG, was able to effectively inhibit the replication and effector function of CD8 + T EM cells. 52 These data suggest that mTOR inhibition as the sole immunosuppressive is not effective at inhibiting alloreactive memory responses, but it could be effective in combination with costimulation blockade as a rescue treatment for acute cellular rejection or even as maintenance immunosuppression.…”

Section: Use Of Steroids and Mammalian Target Of Rapamycin Inhibitorsmentioning

confidence: 99%

The Entangled World of Memory T Cells and Implications in Transplantation

Alexander

Ford

2023

Transplantation

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Memory T cells that are specific for alloantigen can arise from a variety of stimuli, ranging from direct allogeneic sensitization from prior transplantation, blood transfusion, or pregnancy to the elicitation of pathogen-specific T cells that are cross-reactive with alloantigen. Regardless of the mechanism by which they arise, alloreactive memory T cells possess key metabolic, phenotypic, and functional properties that render them distinct from naive T cells. These properties affect the immune response to transplantation in 2 important ways: first, they can alter the speed, location, and effector mechanisms with which alloreactive T cells mediate allograft rejection, and second, they can alter T-cell susceptibility to immunosuppression. In this review, we discuss recent developments in understanding these properties of memory T cells and their implications for transplantation.

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Section: Use Of Steroids and Mammalian Target Of Rapamycin Inhibitorsmentioning

confidence: 99%

The Entangled World of Memory T Cells and Implications in Transplantation

Alexander

Ford

2023

Transplantation

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“…Rapamycin has also shown its superiority over tacrolimus with respect to inhibiting B cell to plasma-cell differentiation [77]. In mice sensitized by prior skin graft, preoperative rapamycin increased the expression of regulatory T cells, but did not prolong the survival of mice after cardiac allotransplantation [78]. In donor skinsensitized mice, those with mTOR deletion in T cells had longer mean survival time (MST 19.5 days) versus wild-type recipients (MST 5.4 days) [75].…”

Section: Replacing Tacrolimusmentioning

confidence: 99%

Optimal Immunosuppression Strategy in the Sensitized Kidney Transplant Recipient

Olaso

Manook

Moris

et al. 2021

JCM

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Patients with previous sensitization events against anti-human leukocyte antigens (HLA) often have circulating anti-HLA antibodies. Following organ transplantation, sensitized patients have higher rates of antibody-mediated rejection (AMR) compared to those who are non-sensitized. More stringent donor matching is required for these patients, which results in a reduced donor pool and increased time on the waitlist. Current approaches for sensitized patients focus on reducing preformed antibodies that preclude transplantation; however, this type of desensitization does not modulate the primed immune response in sensitized patients. Thus, an optimized maintenance immunosuppressive regimen is necessary for highly sensitized patients, which may be distinct from non-sensitized patients. In this review, we will discuss the currently available therapeutic options for induction, maintenance, and adjuvant immunosuppression for sensitized patients.

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Inhibition of interferon regulatory factor 4 orchestrates T cell dysfunction, extending mouse cardiac allograft survival

Yuan,

Zhang,

Peng

et al. 2024

Chinese Medical Journal

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Background: T cell dysfunction, which includes exhaustion, anergy, and senescence, is a distinct T cell differentiation state that occurs after antigen exposure. Although T cell dysfunction has been a cornerstone of cancer immunotherapy, its potential in transplant research, while not yet as extensively explored, is attracting growing interest. Interferon regulatory factor 4 (IRF4) has been shown to play a pivotal role in inducing T cell dysfunction. Methods: A novel ultra-low-dose combination of Trametinib and Rapamycin, targeting IRF4 inhibition, was employed to investigate T cell proliferation, apoptosis, cytokine secretion, expression of T-cell dysfunction-associated molecules, effects of MAPK and mammalian target of Rapamycin (mTOR) signaling pathways, and allograft survival in both in vitro and BALB/c to C57BL/6 mouse cardiac transplantation models. Results: In vitro, blockade of IRF4 in T cells effectively inhibited T cell proliferation, increased apoptosis, and significantly upregulated the expression of programmed cell death protein 1 (PD-1), Helios, CD160, and cytotoxic T lymphocyte-associated antigen (CTLA-4), markers of T cell dysfunction. Furthermore, it suppressed the secretion of pro-inflammatory cytokines interferon (IFN)-γ and interleukin (IL)-17. Combining ultra-low-dose Trametinib (0.1 mg·kg−1·day−1) and Rapamycin (0.1 mg·kg−1·day−1) demonstrably extended graft survival, with 4 out of 5 mice exceeding 100 days post-transplantation. Moreover, analysis of grafts at day 7 confirmed sustained IFN regulatory factor 4 (IRF4) inhibition, enhanced PD-1 expression, and suppressed IFN-γ secretion, reinforcing the in vivo efficacy of this IRF4-targeting approach. The combination of Trametinib and Rapamycin synergistically inhibited the MAPK and mTOR signaling network, leading to a more pronounced suppression of IRF4 expression. Conclusions: Targeting IRF4, a key regulator of T cell dysfunction, presents a promising avenue for inducing transplant immune tolerance. In this study, we demonstrate that a novel ultra-low-dose combination of Trametinib and Rapamycin synergistically suppresses the MAPK and mTOR signaling network, leading to profound IRF4 inhibition, promoting allograft acceptance, and offering a potential new therapeutic strategy for improved transplant outcomes. However, further research is necessary to elucidate the underlying pharmacological mechanisms and facilitate translation to clinical practice.

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Preoperative application of combination of portal venous injection of donor spleen cells and intraperitoneal injection of rapamycin prolongs the survival of cardiac allografts in mice

Cited by 3 publications

References 21 publications

The Entangled World of Memory T Cells and Implications in Transplantation

The Entangled World of Memory T Cells and Implications in Transplantation

Optimal Immunosuppression Strategy in the Sensitized Kidney Transplant Recipient

Inhibition of interferon regulatory factor 4 orchestrates T cell dysfunction, extending mouse cardiac allograft survival

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