The Potential Clinical Application of Induced Tolerogenic Macrophages : Transplantation

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The Potential Clinical Application of Induced Tolerogenic Macrophages

Xu, Hong MD1; Suire, Colby PhD1; Ildstad, Suzanne T. MD1,2

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Transplantation 107(1):p 23-24, January 2023. | DOI: 10.1097/TP.0000000000004246
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Immune cell therapy has several potential applications, including treatment of cancers and autoimmune disease, tissue regeneration, and promotion of immune tolerance. Currently, several regulatory immune cell populations have emerged to be of great interest as a potential therapy in organ transplantation to promote transplant tolerance and prevent graft rejection. These therapies hold the promise of prolonging graft survival while minimizing treatment-related toxicity. In allogeneic hematopoietic stem cell transplantation (HSCT), several cell types, including regulatory T cells, mesenchymal stromal cells, and myeloid derived suppressor cells, have been identified to have the potential to treat acute and chronic graft-versus-host disease (GvHD).1

GvHD is a major transplant-related complication leading to increased morbidity and mortality following allogeneic HSCT.2 GvHD occurs when donor T cells alloreactive to host major histocompatibility antigens attack host tissues and organs. The critical role of T cells in mediating acute GvHD is evidenced by abrogation of GvHD when donor T cells are removed from the graft before transplantation. However, removal of T cells can impair not only HSC engraftment but also T cell–mediated graft-versus-leukemia effects. Conventional immunosuppression does not sufficiently treat GvHD, especially in HLA-mismatched transplant recipients. Therefore, novel therapies are needed for better management of GvHD.

Fibroblastic reticular cells (FRCs) are specialized stromal cells notably localized in secondary lymphoid organs that have been demonstrated to interact directly with the immune system. FRCs have been shown to regulate adaptive immune responses through various immune modulating mechanisms,3 including regulation of T-cell migration, survival, and maintenance of peripheral immune tolerance. Tolerogenic macrophages actively participate in T-cell immune regulation.4 The publication by Liu et al5 in this issue of Transplantation sought to define the relationship between FRCs and lymph node macrophages for their tolerogenic roles using in vitro culture system and in vivo mouse models. Their data provide evidence suggesting that lymph nodes FRC-induce regulatory macrophages at an early stage post–allo-HSCT. These FRC-induced macrophages displayed typical macrophage morphology and an immunophenotype based on CD11b+F4/80+ cell surface markers and high expression of PD-L1, an immune checkpoint inhibitor. These findings are consistent with previous studies conducted to define ex vivo–generated regulatory macrophages.6 Liu et al5 further elucidated the role of macrophage colony-stimulating factor (M-CSF) as a critical cytokine for the induction of regulatory macrophages. FRC-induced macrophages inhibited T-cell activation and differentiation toward Th1/Tc1 cells ex vivo. Most importantly, the immunoregulatory function of these induced regulatory macrophages demonstrated an ability to effectively attenuate acute GvHD in vivo.

This study has revealed a novel mechanism underpinning the role of the microenvironment in secondary lymphoid organs, specifically highlighting the interactions between FRCs and macrophages for immune tolerogenic regulation. Various aspects of lymph node FRCs and their role in inducing regulatory macrophages to treat or prevent GvHD remains to be fully elucidated. Understanding the mechanisms by which induced regulatory macrophages alleviate GvHD will be critical for clinical implementation of this approach as a regulatory cell therapy product. The mechanisms of GvHD attenuation have been shown directly by FRC-induced macrophages inhibited T-cell activation and differentiation in current study. The indirect mechanism of regulatory macrophages on GvHD may be attributed to their role in the conversion of CD4+ T cells to IL-10+TIGIT+ FoxP3+ regulatory T cells (Treg) as demonstrated by Riquelme et al.7 Their work elegantly demonstrated that human regulatory macrophage can induce Treg, which suppress bystander T-cell proliferation and inhibit dendritic cell maturation. Moreover, preoperative administration of regulatory macrophages results in an increase in circulating TIGIT+ Treg in living-donor kidney transplantation. Additional studies in humans by Hutchinson et al8 further demonstrated the feasibility and safety of regulatory macrophages as a cell therapy product. These clinical studies in humans represent a promising frontier in preventing or reducing GvHD and tolerance induction in solid organ transplant recipients. However, numerous hurdles will first need to be overcome for the therapy of FRC-induced regulatory macrophages to become a clinical reality.

Several preclinical studies and clinical trials have demonstrated reduction and/or prevention of GvHD when immune regulatory cells are coinfused with HSC following conditioning. However, a current unmet medical need is the development of a cellular therapy that can be used to treat GvHD when it occurs. One hurdle that will need to be overcome for the clinical application of induced regulatory macrophages in treating GvHD is in obtaining sufficient number of cells for therapy. The current study by Lui et al5 demonstrated that FRC macrophages induced ex vivo from BMC possesses the potential for immunosuppressive capacity and M-CSF was the critical cytokine for FRC to induce macrophages.5 M-CSF was found to be highly expressed in FRC, but further study needs to define the accurate source of M-CSF at local stromal environment in lymph nodes including endothelial cells, follicular dendritic cells, marginal reticular cells, and fibroblastic FRCs. The ex vivo generation of tolerogenic macrophages may help ensure sufficient cells for the use of this therapy in the clinic.

Although the use of ex vivo–generated regulatory macrophages represent a promising prospect for cell therapy, several additional challenges will need to be overcome.9 Among these challenges is the need to evaluate ex vivo-generated regulatory macrophages for their immunogenicity because they should not initiate proinflammatory responses or cause sensitization in allogeneic recipients. Furthermore, it will be critical to ensure manufacturing and release testing control to maintain cellular phenotype and immunomodulatory function. The immunosuppressive function will also require additional assessment to avoid nonspecific effects leading to increased infection or tumor formation. The homing of induced regulatory macrophages has been studied clinically and these cells after central venous administration were observed to traffic from lungs to liver, spleen, and hematopoietically active bone marrow.10 The feasibility of translating FRC-induced macrophages to a clinical cell therapy product for allogeneic solid organ transplantation has been underpinned by several clinical pilot studies.8 Taken together, the study by Liu et al5 provides important preclinical insight into the role FRCs play in promoting regulatory macrophages and their role in alleviating the risk of GvHD in allogeneic HSC transplantation.


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