ACTH treatment promotes murine cardiac allograft acceptance

Zhao, Jing; Jiang, Liwei; Uehara, Mayuko; Banouni, Naima; Dulaijan, Basmah S. Al; Azzi, Jamil; Ichimura, Takaharu; Li, Xiaofei; Jarolím, Petr; Fiorina, Paolo; Tullius, Stefan G.; Madsen, Joren C.; Kasinath, Vivek; Abdi, Reza

doi:10.1172/jci.insight.143385

Cited by 6 publications

(5 citation statements)

References 122 publications

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“…Mouse heterotopic cardiac transplantation and skin transplantation. Vascularized intra-abdominal heterotopic transplantation of heart allografts and skin transplantation were performed using microsurgical techniques, as previously described (3,63,(132)(133)(134). The status of the heart allograft was monitored daily by abdominal palpation.…”

Section: Methodsmentioning

confidence: 99%

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Delivery of costimulatory blockade to lymph nodes promotes transplant acceptance in mice

Zhao¹,

Jung²,

Li³

et al. 2022

Journal of Clinical Investigation

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The lymph node (LN) is the primary site of alloimmunity activation and regulation during transplantation. Here, we investigated how fibroblastic reticular cells (FRCs) facilitate the tolerance induced by anti-CD40L in a murine model of heart transplantation. We found that both the absence of LNs and FRC depletion abrogated the effect of anti-CD40L in prolonging murine heart allograft survival. Depletion of FRCs impaired homing of T cells across the high endothelial venules (HEVs) and promoted formation of alloreactive T cells in the LNs in heart-transplanted mice treated with anti-CD40L. Single-cell RNA sequencing of the LNs showed that anti-CD40L promotes a Madcam1 + FRC subset. FRCs also promoted the formation of regulatory T cells (Tregs) in vitro. Nanoparticles (NPs) containing anti-CD40L were selectively delivered to the LNs by coating them with MECA-79, which binds to peripheral node addressin (PNAd) glycoproteins expressed exclusively by HEVs. Treatment with these MECA-79–anti-CD40L-NPs markedly delayed the onset of heart allograft rejection and increased the presence of Tregs. Finally, combined MECA-79–anti-CD40L-NPs and rapamycin treatment resulted in markedly longer allograft survival than soluble anti-CD40L and rapamycin. These data demonstrate that FRCs are critical to facilitating costimulatory blockade. LN-targeted nanodelivery of anti-CD40L could effectively promote heart allograft acceptance.

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Section: Methodsmentioning

confidence: 99%

“…Histological scoring and measurement. Histological scoring of H&E-stained heart allografts was performed using a modified method from the International Society for Heart and Lung Transplantation (139,140), as described previously (63,133). Cellular infiltration was graded from 0 to 4.…”

Section: Methodsmentioning

confidence: 99%

Delivery of costimulatory blockade to lymph nodes promotes transplant acceptance in mice

Zhao¹,

Jung²,

Li³

et al. 2022

Journal of Clinical Investigation

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“…In fact, although MC2R is selective for ACTH, the possibility of cross-binding of other MCRs, such as MC3R (100), on immune cells has decreased the reliability of studies on MC2R −/− mice. Very recently, MC2R expression was confirmed on T regulatory Lymphocytes, and ACTH therapy was shown to promote allograft acceptance after heart transplant in mice (101). This supports a tolerogenic role of ACTH in inflammation, that would partially explain the efficacy in inflammatory diseases such as gout.…”

Section: Immune System and Inflammationmentioning

confidence: 74%

Non-Canonical Effects of ACTH: Insights Into Adrenal Insufficiency

et al. 2021

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IntroductionAdrenocorticotropic hormone (ACTH) is produced from proopiomelanocortin, which is predominantly synthetized in the corticotroph and melanotroph cells of the anterior and intermediate lobes of the pituitary gland and the arcuate nucleus of the hypothalamus. Although ACTH clearly has an effect on adrenal homeostasis and maintenance of steroid hormone production, it also has extra-adrenal effects that require further elucidation.MethodsWe comprehensively reviewed English language articles, regardless of whether they reported the presence or absence of adrenal and extra-adrenal ACTH effects.ResultsIn the present review, we provide an overview on the current knowledge on adrenal and extra-adrenal effects of ACTH. In the section on adrenal ACTH effects, we focused on corticosteroid rhythmicity and effects on steroidogenesis, mineralocorticoids and adrenal growth. In the section on extra-adrenal effects, we have analyzed the effects of ACTH on the osteoarticular and reproductive systems, adipocytes, immune system, brain and skin. Finally, we focused on adrenal insufficiency.ConclusionsThe role of ACTH in maintaining the function of the hypothalamic–pituitary–adrenal axis is well known. Conversely, if we broaden our vision and analyze its role as a potential treatment strategy in other conditions, it will be evident in the literature that researchers seem to have abandoned this aspect in studies conducted several years ago. We believe it is worth re-evaluating the role of ACTH considering its noncanonical effects on the adrenal gland itself and on extra-adrenal organs and tissues; however, this would not have been possible without the recent advances in the pertinent technologies.

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“…One of the endogenous pro-resolving pathways that has extensively been studied at the preclinical and clinical levels, and indeed has reached approval for use in humans, is the targeting of the melanocortin pathway ( 13 ). This system comprises a family of five membrane receptors and four endogenous agonists which, among other functions, have demonstrated anti-inflammatory and pro-resolving actions in various models of disease, including arthritis ( 14 – 16 ), gout ( 17 ), intestinal inflammation ( 18 , 19 ), atherosclerosis ( 20 ), uveitis ( 21 ), transplant rejection ( 22 ), or neuroinflammation ( 23 ) among others. Their role in controlling fibroblast activation have also been studied, and this includes in vitro , in vivo , and clinical investigations.…”

Section: Introductionmentioning

confidence: 99%

Melanocortin therapies to resolve fibroblast-mediated diseases

et al. 2023

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Stromal cells have emerged as central drivers in multiple and diverse diseases, and consequently, as potential new cellular targets for the development of novel therapeutic strategies. In this review we revise the main roles of fibroblasts, not only as structural cells but also as players and regulators of immune responses. Important aspects like fibroblast heterogeneity, functional specialization and cellular plasticity are also discussed as well as the implications that these aspects may have in disease and in the design of novel therapeutics. An extensive revision of the actions of fibroblasts on different conditions uncovers the existence of numerous diseases in which this cell type plays a pathogenic role, either due to an exacerbation of their 'structural' side, or a dysregulation of their 'immune side'. In both cases, opportunities for the development of innovative therapeutic approaches exist. In this regard, here we revise the existing evidence pointing at the melanocortin pathway as a potential new strategy for the treatment and management of diseases mediated by aberrantly activated fibroblasts, including scleroderma or rheumatoid arthritis. This evidence derives from studies involving models of in vitro primary fibroblasts, in vivo models of disease as well as ongoing human clinical trials. Melanocortin drugs, which are pro-resolving mediators, have shown ability to reduce collagen deposition, activation of myofibroblasts, reduction of pro-inflammatory mediators and reduced scar formation. Here we also discuss existing challenges, both in approaching fibroblasts as therapeutic targets, and in the development of novel melanocortin drug candidates, that may help advance the field and deliver new medicines for the management of diseases with high medical needs.

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ACTH treatment promotes murine cardiac allograft acceptance

Cited by 6 publications

References 122 publications

Delivery of costimulatory blockade to lymph nodes promotes transplant acceptance in mice

Delivery of costimulatory blockade to lymph nodes promotes transplant acceptance in mice

Non-Canonical Effects of ACTH: Insights Into Adrenal Insufficiency

Melanocortin therapies to resolve fibroblast-mediated diseases

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