Matthew J. Hartwell, Umut Özbek, Ernst Holler, Anne S. Renteria, Hannah Major-Monfried, Pavan Reddy, Mina Aziz, William J. Hogan, Francis Ayuk, Yvonne A. Efebera, Elizabeth O. Hexner, Udomsak Bunworasate, Muna Qayed, Rainer Ordemann, Matthias Wölfl, Stephan Mielke, Attaphol Pawarode, Yi-Bin Chen, Steven Devine, Andrew C. Harris, Madan Jagasia, Carrie L. Kitko, Mark R. Litzow, Nicolaus Kröger, Franco Locatelli, George Morales, Ryotaro Nakamura, Ran Reshef, Wolf Rösler, Daniela Weber, Kitsada Wudhikarn, Gregory A. Yanik, John E. Levine, James L.M. Ferrara
Rat and human CD4+ and CD8+ Tregs expressing low levels of CD45RC have strong immunoregulatory properties. We describe here that human CD45 isoforms are nonredundant and identify distinct subsets of cells. We show that CD45RC is not expressed by CD4+ and CD8+ Foxp3+ Tregs, while CD45RA/RB/RO are. Transient administration of a monoclonal antibody (mAb) targeting CD45RC in a rat cardiac allotransplantation model induced transplant tolerance associated with inhibition of allogeneic humoral responses but maintained primary and memory responses against cognate antigens. Anti-CD45RC mAb induced rapid death of CD45RChigh T cells through intrinsic cell signaling but preserved and potentiated CD4+ and CD8+ CD45RClow/– Tregs, which are able to adoptively transfer donor-specific tolerance to grafted recipients. Anti-CD45RC treatment results in distinct transcriptional signature of CD4+ and CD8+ CD45RClow/– Tregs. Finally, we demonstrate that anti-human CD45RC treatment inhibited graft-versus-host disease (GVHD) in immune-humanized NSG mice. Thus, short-term anti-CD45RC is a potent therapeutic candidate to induce transplantation tolerance in human.
Elodie Picarda, Séverine Bézie, Laetitia Boucault, Elodie Autrusseau, Stéphanie Kilens, Dimitri Meistermann, Bernard Martinet, Véronique Daguin, Audrey Donnart, Eric Charpentier, Laurent David, Ignacio Anegon, Carole Guillonneau
Rebecca A. Sosa, Ali Zarrinpar, Maura Rossetti, Charles R. Lassman, Bita V. Naini, Nakul Datta, Ping Rao, Nicholas Harre, Ying Zheng, Roberto Spreafico, Alexander Hoffmann, Ronald W. Busuttil, David W. Gjertson, Yuan Zhai, Jerzy W. Kupiec-Weglinski, Elaine F. Reed
Regulatory T cells (Tregs) play a crucial role in the maintenance of peripheral tolerance. Quantitative and/or qualitative defects in Tregs result in diseases such as autoimmunity, allergy, malignancy, and graft-versus-host disease (GVHD), a serious complication of allogeneic stem cell transplantation (SCT). We recently reported increased expression of autophagy-related genes (
Laëtitia Le Texier, Katie E. Lineburg, Benjamin Cao, Cameron McDonald-Hyman, Lucie Leveque-El Mouttie, Jemma Nicholls, Michelle Melino, Blessy C. Nalkurthi, Kylie A. Alexander, Bianca Teal, Stephen J. Blake, Fernando Souza-Fonseca-Guimaraes, Christian R. Engwerda, Rachel D. Kuns, Steven W. Lane, Michele Teng, Charis Teh, Daniel Gray, Andrew D. Clouston, Susan K. Nilsson, Bruce R. Blazar, Geoffrey R. Hill, Kelli P.A. MacDonald
It is well established that maladaptive innate immune responses to sterile tissue injury represent a fundamental mechanism of disease pathogenesis. In the context of cardiac ischemia reperfusion injury, neutrophils enter inflamed heart tissue, where they play an important role in potentiating tissue damage and contributing to contractile dysfunction. The precise mechanisms that govern how neutrophils are recruited to and enter the injured heart are incompletely understood. Using a model of cardiac transplant–mediated ischemia reperfusion injury and intravital 2-photon imaging of beating mouse hearts, we determined that tissue-resident CCR2+ monocyte–derived macrophages are essential mediators of neutrophil recruitment into ischemic myocardial tissue. Our studies revealed that neutrophil extravasation is mediated by a TLR9/MyD88/CXCL5 pathway. Intravital 2-photon imaging demonstrated that CXCL2 and CXCL5 play critical and nonredundant roles in guiding neutrophil adhesion and crawling, respectively. Together, these findings uncover a specific role for a tissue-resident monocyte-derived macrophage subset in sterile tissue inflammation and support the evolving concept that macrophage ontogeny is an important determinant of function. Furthermore, our results provide the framework for targeting of cell-specific signaling pathways in myocardial ischemia reperfusion injury.
Wenjun Li, Hsi-Min Hsiao, Ryuji Higashikubo, Brian T. Saunders, Ankit Bharat, Daniel R. Goldstein, Alexander S. Krupnick, Andrew E. Gelman, Kory J. Lavine, Daniel Kreisel
The efficacy of allogeneic hematopoietic stem cell transplantation for hematologic malignancies is limited by the difficulty in suppressing graft-versus-host disease (GVHD) without compromising graft-versus-tumor (GVT) effects. We previously showed that RAS/MEK/ERK signaling depends on memory differentiation in human T cells, which confers susceptibility to selective inhibition of naive T cells. Actually, antineoplastic MEK inhibitors selectively suppress alloreactive T cells, sparing virus-specific T cells in vitro. Here, we show that trametinib, a MEK inhibitor clinically approved for melanoma, suppresses GVHD safely without affecting GVT effects in vivo. Trametinib prolonged survival of GVHD mice and attenuated GVHD symptoms and pathology in the gut and skin. It inhibited ERK1/2 phosphorylation and expansion of donor T cells, sparing Tregs and B cells. Although high-dose trametinib inhibited myeloid cell engraftment, low-dose trametinib suppressed GVHD without severe adverse events. Notably, trametinib facilitated the survival of mice transplanted with allogeneic T cells and P815 tumor cells with no residual P815 cells observed in the livers and spleens, whereas tacrolimus resulted in P815 expansion. These results confirm that trametinib selectively suppresses GVHD-inducing T cells while sparing antitumor T cells in vivo, which makes it a promising candidate for translational studies aimed at preventing or treating GVHD.
Hidekazu Itamura, Takero Shindo, Isao Tawara, Yasushi Kubota, Ryusho Kariya, Seiji Okada, Krishna V. Komanduri, Shinya Kimura
Cardiovascular progenitor cells (CPCs) expressing the ISL1-LIM–homeodomain transcription factor contribute developmentally to cardiomyocytes in all 4 chambers of the heart. Here, we show that ISL1-CPCs can be applied to myocardial regeneration following injury. We used a rapid 3D methylcellulose approach to form murine and human ISL1-CPC spheroids that engrafted after myocardial infarction in murine hearts, where they differentiated into cardiomyocytes and endothelial cells, integrating into the myocardium and forming new blood vessels. ISL1-CPC spheroid–treated mice exhibited reduced infarct area and increased blood vessel formation compared with control animals. Moreover, left ventricular (LV) contractile function was significantly better in mice transplanted with ISL1-CPCs 4 weeks after injury than that in control animals. These results provide proof-of-concept of a cardiac repair strategy employing ISL1-CPCs that, based on our previous lineage-tracing studies, are committed to forming heart tissue, in combination with a robust methylcellulose spheroid–based delivery approach.
Oscar Bartulos, Zhen Wu Zhuang, Yan Huang, Nicole Mikush, Carol Suh, Alda Bregasi, Lin Wang, William Chang, Diane S. Krause, Lawrence H. Young, Jordan S. Pober, Yibing Qyang
Successful induction of allograft tolerance has been achieved in nonhuman primates (NHPs) and humans via induction of transient hematopoietic chimerism. Since allograft tolerance was achieved in these recipients without durable chimerism, peripheral mechanisms are postulated to play a major role. Here, we report our studies of T cell immunity in NHP recipients that achieved long-term tolerance versus those that rejected the allograft (AR). All kidney, heart, and lung transplant recipients underwent simultaneous or delayed donor bone marrow transplantation (DBMT) following conditioning with a nonmyeloablative regimen. After DBMT, mixed lymphocyte culture with CFSE consistently revealed donor-specific loss of CD8+ T cell responses in tolerant (TOL) recipients, while marked CD4+ T cell proliferation in response to donor antigens was found to persist. Interestingly, a significant proportion of the proliferated CD4+ cells were FOXP3+ in TOL recipients, but not in AR or naive NHPs. In TOL recipients, CD4+FOXP3+ cell proliferation against donor antigens was greater than that observed against third-party antigens. Finally, the expanded Tregs appeared to be induced Tregs (iTregs) that were converted from non-Tregs. These data provide support for the hypothesis that specific induction of iTregs by donor antigens is key to long-term allograft tolerance induced by transient mixed chimerism.
Kiyohiko Hotta, Akihiro Aoyama, Tetsu Oura, Yohei Yamada, Makoto Tonsho, Kyu Ha Huh, Kento Kawai, David Schoenfeld, James S. Allan, Joren C. Madsen, Gilles Benichou, Rex-Neal Smith, Robert B. Colvin, David H. Sachs, A. Benedict Cosimi, Tatsuo Kawai
Immune-suppressed organ transplant recipients (OTRs) can develop catastrophic squamous cell carcinoma (SCC), characterized by multiple primary tumors, extensive body surface area involvement, or metastases. There are currently no curative systemic therapies available. We previously showed that IL-22 enhances SCC proliferation. Herein, we examined links between cyclosporine (CSA), IL-22, and SCC in patients, cell lines, and mice with UV light–induced SCC. Eighteen of 114 OTRs developed catastrophic SCC, which was strongly associated with CSA treatment. We found that CSA drives T cell polarization toward IL-22–producing T22 cells, and CSA treatment increased IL-22 receptor in SCC cells. SCC tissue from OTRs showed increased expression of IL-22RA1. CSA potentiated rescue by IL-22 of serum-starved SCC cells; treatment of SCC cells with IL-22 and CSA increased both their migratory and invasive capacity. In a UV-induced model of SCC in SKH-1 immunocompetent mice, treatment with anti–IL-22 antibody reduced tumor number and tumor burden. We found that catastrophic SCC in OTRs is associated with CSA use, which may be acting by favoring T22 polarization. Since anti–IL-22 antibody administration decreased tumor number and tumor burden in vivo, blockade of the IL-22 axis may be developed as a viable therapeutic option for catastrophic SCC.
Melody Abikhair, Hiroshi Mitsui, Valerie Yanofsky, Nazanin Roudiani, Channa Ovits, Teddy Bryan, Tatiana M. Oberyszyn, Kathleen L. Tober, Juana Gonzalez, James G. Krueger, Diane Felsen, John A. Carucci
Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA.
Maria Lucia L. Madariaga, Philip J. Spencer, Kumaran Shanmugarajah, Kerry A. Crisalli, David C. Chang, James F. Markmann, Nahel Elias, A. Benedict Cosimi, David H. Sachs, Tatsuo Kawai
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