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4. Advancing mouse models for transplantation research

Author

Cravedi, Paolo, Riella, Leonardo V., Ford, Mandy L., Valujskikh, Anna, Menon, Madhav C., Kirk, Allan D., Alegre, Maria-Luisa, Alessandrini, Alessandro, Feng, Sandy, Kehn, Patricia, Najafian, Nader, Hancock, Wayne W., Heeger, Peter S., Maltzman, Jonathan S., Mannon, Roslyn B., Nadig, Satish N., Odim, Jonah, Turnquist, Heth, Shaw, Julia, West, Lori, Luo, Xunrong, Chong, Anita S., and Bromberg, Jonathan S.

Published
2024
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11. Simultaneous targeting of primary tumor, draining lymph node, and distant metastases through high endothelial venule-targeted delivery

Author

Jiang, Liwei, Jung, Sungwook, Zhao, Jing, Kasinath, Vivek, Ichimura, Takaharu, Joseph, John, Fiorina, Paolo, Liss, Andrew S, Shah, Khalid, Annabi, Nasim, Joshi, Nitin, Akama, Tomoya O, Bromberg, Jonathan S, Kobayashi, Motohiro, Uchimura, Kenji, and Abdi, Reza

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Biotechnology, Cancer, Targeting delivery, Caner therapy, HEV antibody, Biomedical Engineering, Nanotechnology, Nanoscience & Nanotechnology, Medical biotechnology, Biomedical engineering
Abstract

Cancer patients with malignant involvement of tumor-draining lymph nodes (TDLNs) and distant metastases have the poorest prognosis. A drug delivery platform that targets the primary tumor, TDLNs, and metastatic niches simultaneously, remains to be developed. Here, we generated a novel monoclonal antibody (MHA112) against peripheral node addressin (PNAd), a family of glycoproteins expressed on high endothelial venules (HEVs), which are present constitutively in the lymph nodes (LNs) and formed ectopically in the tumor stroma. MHA112 was endocytosed by PNAd-expressing cells, where it passed through the lysosomes. MHA112 conjugated antineoplastic drug Paclitaxel (Taxol) (MHA112-Taxol) delivered Taxol effectively to the HEV-containing tumors, TDLNs, and metastatic lesions. MHA112-Taxol treatment significantly reduced primary tumor size as well as metastatic lesions in a number of mouse and human tumor xenografts tested. These data, for the first time, indicate that human metastatic lesions contain HEVs and provide a platform that permits simultaneous targeted delivery of antineoplastic drugs to the three key sites of primary tumor, TDLNs, and metastases.

Published
2021

12. Ectopic high endothelial venules in pancreatic ductal adenocarcinoma: A unique site for targeted delivery

Author

Bahmani, Baharak, Uehara, Mayuko, Ordikhani, Farideh, Li, Xiaofei, Jiang, Liwei, Banouni, Naima, Ichimura, Takaharu, Kasinath, Vivek, Eskandari, Siawosh K, Annabi, Nasim, Bromberg, Jonathan S, Shultz, Leonard D, Greiner, Dale L, and Abdi, Reza

Subjects
Medical Biotechnology, Biomedical and Clinical Sciences, Rare Diseases, Pancreatic Cancer, Digestive Diseases, Nanotechnology, Bioengineering, Cancer, Development of treatments and therapeutic interventions, Aetiology, 5.1 Pharmaceuticals, 2.1 Biological and endogenous factors, Good Health and Well Being, Animals, Antineoplastic Agents, Biomarkers, Carcinoma, Pancreatic Ductal, Cell Line, Disease Models, Animal, Endothelium, Lymphatic, Female, Humans, Immunohistochemistry, Lymph Nodes, Male, Mice, Molecular Targeted Therapy, Nanoparticles, Neovascularization, Pathologic, Paclitaxel, Pancreatic Neoplasms, Theranostic Nanomedicine, Xenograft Model Antitumor Assays, Pancreatic ductal adenocarcinoma, High endothelial venules, Peripheral node addressin, MECA79 coated nanoparticles, Taxol, Clinical Sciences, Public Health and Health Services, Clinical sciences, Epidemiology
Abstract

BackgroundNanomedicine offers an excellent opportunity to tackle treatment-refractory malignancies by enhancing the delivery of therapeutics to the tumor site. High endothelial venules (HEVs) are found primarily in lymph nodes or formed de novo in peripheral tissues during inflammatory responses. They express peripheral node addressin (PNAd), which is recognized by the monoclonal antibody MECA79.MethodsHere, we demonstrated that HEVs form de novo in human pancreatic ductal adenocarcinoma (PDAC). We engineered MECA79 coated nanoparticles (MECA79-NPs) that recognize these ectopic HEVs in PDAC.FindingsThe trafficking of MECA79-NPs following intravenous delivery to human PDAC implanted in a humanized mouse model was more robust than non-conjugated NPs. Treatment with MECA79-Taxol-NPs augmented the delivery of Paclitaxel (Taxol) to the tumor site and significantly reduced the tumor size. This effect was associated with a higher apoptosis rate of PDAC cells and reduced vascularization within the tumor.InterpretationTargeting the HEVs of PDAC using MECA79-NPs could lay the ground for the localized delivery of a wide variety of drugs including chemotherapeutic agents. FUND: National Institutes of Health (NIH) grants: T32-EB016652 (B·B.), NIH Cancer Core Grant CA034196 (L.D.S.), National Institute of Allergy and Infectious Diseases grants R01-AI126596 and R01-HL141815 (R.A.).

Published
2018

13. Natural Antibodies Are Associated With Rejection and Long-term Renal Allograft Loss in a Multicenter International Cohort

Author

See, Sarah B., Yang, Xue, Burger, Carole, Lamarthée, Baptiste, Snanoudj, Renaud, Shihab, Ronzon, Tsapepas, Demetra S., Roy, Poulomi, Larivière-Beaudoin, Stéphanie, Hamelin, Katia, Mendoza Rojas, Aleixandra, van Besouw, Nicole M., Bartosic, Amanda, Daniel, Nikita, Rodica, Vasilescu E., Mohan, Sumit, Cohen, David, Ratner, Lloyd, Baan, Carla C., Bromberg, Jonathan S., Cardinal, Héloïse, Anglicheau, Dany, Sun, Yifei, and Zorn, Emmanuel

Published
2023
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15. Clinical outcomes from the Assessing Donor-derived cell-free DNA Monitoring Insights of kidney Allografts with Longitudinal surveillance (ADMIRAL) study

Author

Bu, Lihong, Gupta, Gaurav, Pai, Akshta, Anand, Sanjiv, Stites, Erik, Moinuddin, Irfan, Bowers, Victor, Jain, Pranjal, Axelrod, David A., Weir, Matthew R., Wolf-Doty, Theresa K., Zeng, Jijiao, Tian, Wenlan, Qu, Kunbin, Woodward, Robert, Dholakia, Sham, De Golovine, Aleskandra, Bromberg, Jonathan S., Murad, Haris, and Alhamad, Tarek

Published
2022
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20. Delivery of costimulatory blockade to lymph nodes promotes transplant acceptance in mice

Author

Zhao, Jing, Jung, Sungwook, Li, Xiaofei, Li, Lushen, Kasinath, Vivek, Zhang, Hengcheng, Movahedi, Said N., Mardini, Ahmad, Sabiu, Gianmarco, Hwang, Yoonha, Saxena, Vikas, Song, Yang, Ma, Bing, Acton, Sophie E., Kim, Pilhan, Madsen, Joren C., Sage, Peter T., Tullius, Stefan G., Tsokos, George C., Bromberg, Jonathan S., and Abdi, Reza

Subjects
T cells -- Genetic aspects -- Health aspects, Immune response -- Genetic aspects, Graft rejection -- Genetic aspects -- Prevention, Health care industry
Abstract

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.sup.+] 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 address in (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., Introduction Lymph nodes (LNs) are integral sites at which the alloimmune response is mounted following transplantation. Our group has shown that LNs also function as sites of immune regulation by [...]

Published
2022
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22. Nomenclature for kidney function and disease: report of a Kidney Disease: Improving Global Outcomes (KDIGO) Consensus Conference

Author

Levey, Andrew S., Eckardt, Kai-Uwe, Dorman, Nijsje M., Christiansen, Stacy L., Hoorn, Ewout J., Ingelfinger, Julie R., Inker, Lesley A., Levin, Adeera, Mehrotra, Rajnish, Palevsky, Paul M., Perazella, Mark A., Tong, Allison, Allison, Susan J., Bockenhauer, Detlef, Briggs, Josephine P., Bromberg, Jonathan S., Davenport, Andrew, Feldman, Harold I., Fouque, Denis, Gansevoort, Ron T., Gill, John S., Greene, Eddie L., Hemmelgarn, Brenda R., Kretzler, Matthias, Lambie, Mark, Lane, Pascale H., Laycock, Joseph, Leventhal, Shari E., Mittelman, Michael, Morrissey, Patricia, Ostermann, Marlies, Rees, Lesley, Ronco, Pierre, Schaefer, Franz, St. Clair Russell, Jennifer, Vinck, Caroline, Walsh, Stephen B., Weiner, Daniel E., Cheung, Michael, Jadoul, Michel, and Winkelmayer, Wolfgang C.

Published
2020
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25. Contemporary incidence and risk factors of post transplant Erythrocytosis in deceased donor kidney transplantation

Author

Alasfar, Sami, Hall, Isaac E., Mansour, Sherry G., Jia, Yaqi, Thiessen-Philbrook, Heather R., Weng, Francis L., Singh, Pooja, Schröppel, Bernd, Muthukumar, Thangamani, Mohan, Sumit, Malik, Rubab F., Harhay, Meera N., Doshi, Mona D., Akalin, Enver, Bromberg, Jonathan S., Brennan, Daniel C., Reese, Peter P., and Parikh, Chirag R.

Published
2021
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27. Lymph node fibroblastic reticular cells deposit fibrosis-associated collagen following organ transplantation

Author

Li, Xiaofei, Zhao, Jing, Kasinath, Vivek, Uehara, Mayuko, Jiang, Liwei, Banouni, Naima, McGrath, Martina M., Ichimura, Takaharu, Fiorina, Paolo, Lemos, Dario R., Shin, Su Ryon, Ware, Carl F., Bromberg, Jonathan S., and Abdi, Reza

Subjects
Heart transplantation -- Analysis, B cells -- Analysis, Collagen -- Analysis, Immune response -- Analysis, Fibrosis -- Analysis, Health care industry
Abstract

Although the immune response within draining lymph nodes (DLNs) has been studied for decades, how their stromal compartment contributes to this process remains to be fully explored. Here, we show that donor mast cells were prominent activators of collagen I deposition by fibroblastic reticular cells (FRCs) in DLNs shortly following transplantation. Serial analysis of the DLN indicated that the LN stroma did not return to its baseline microarchitecture following organ rejection and that the DLN contained significant fibrosis following repetitive organ transplants. Using several FRC conditional-knockout mice, we show that induction of senescence in the FRCs of the DLN resulted in massive production of collagen I and a proinflammatory milieu within the DLN. Stimulation of herpes virus entry mediator (HVEM) on FRCs by its ligand LIGHT contributed chiefly to the induction of senescence in FRCs and overproduction of collagen I. Systemic administration of ex vivo-expanded FRCs to mice decreased DLN fibrosis and strengthened the effect of anti-CD40L in prolonging heart allograft survival. These data demonstrate that the transformation of FRCs into proinflammatory myofibroblasts is critically important for the maintenance of a proinflammatory milieu within a fibrotic DLN., Introduction Lymph nodes (LNs) are the quintessential organs of alloimmunity following transplantation. Recent advances in elucidating the function of specific cellular and stromal compartments in the LN have broadened our [...]

Published
2020
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28. The lymph node stromal laminin [alpha]5 shapes alloimmunity

Author

Li, Lushen, Shirkey, Marina W., Zhang, Tianshu, Xiong, Yanbao, Piao, Wenji, Saxena, Vikas, Paluskievicz, Christina, Lee, Young, Toney, Nicholas, Cerel, Benjamin M., Li, Qinshan, Simon, Thomas, Smith, Kyle D., Hippen, Keli L., Blazar, Bruce R., Abdi, Reza, and Bromberg, Jonathan S.

Subjects
Thermo Fisher Scientific Inc., Antigens, Laminin, B cells, Integrins, Hybrid vehicles, Scientific equipment industry, T cells, Surgery, Lymphocytes, Transplantation, Cell differentiation, Phenotypes, Human migration, Endothelium, Brain, Homografts, Immune response, Health care industry
Abstract

Lymph node stromal cells (LNSCs) regulate immunity through constructing lymphocyte niches. LNSC-produced laminin [alpha]5 (Lama5) regulates [CD4.sup.+] T cells but the underlying mechanisms of its functions are poorly understood. Here we show that depleting Lama5 in LNSCs resulted in decreased Lama5 protein in the LN cortical ridge (CR) and around high endothelial venules (HEVs). Lama5 depletion affected LN structure with increased HEVs, upregulated chemokines, and cell adhesion molecules, and led to greater numbers of Tregs in the T cell zone. Mouse and human T cell transendothelial migration and T cell entry into LNs were suppressed by Lama5 through the receptors [alpha]6 integrin and [alpha]-dystroglycan. During immune responses and allograft transplantation, depleting Lama5 promoted antigen-specific [CD4.sup.+] T cell entry into the CR through HEVs, suppressed T cell activation, and altered T cell differentiation to suppressive regulatory phenotypes. Enhanced allograft acceptance resulted from depleting Lama5 or blockade of T cell Lama5 receptors. Lama5 and Lama4/Lama5 ratios in allografts were associated with the rejection severity. Overall, our results demonstrated that stromal Lama5 regulated immune responses through altering LN structures and T cell behaviors. This study delineated a stromal Lama5-T cell receptor axis that can be targeted for immune tolerance modulation., Introduction The lymph node (LN) is the central hub that exchanges antigen-presenting cells and immune cells with peripheral tissues or blood, permitting T cells to encounter cognate antigens and orchestrating [...]

Published
2020
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30. Lymph node fibroblastic reticular cells preserve a tolerogenic niche in allograft transplantation through laminin [alpha]4

Author

Li, Lushen, Shirkey, Marina W., Zhang, Tianshu, Piao, Wenji, Li, Xiaofei, Zhao, Jing, Mei, Zhongcheng, Guo, Yizhan, Saxena, Vikas, Kensiski, Allison, Gavzy, Samuel J., Song, Yang, Ma, Bing, Wu, Jing, Xiong, Yanbao, Wu, Long, Fan, Xiaoxuan, Roussey, Holly, Li, Meng, Krupnick, Alexxander S., Abdi, Reza, and Bromberg, Jonathan S.

Subjects
Lungs -- Transplantation, Medical research, Medicine, Experimental, Lymph nodes -- Physiological aspects -- Health aspects, Laminin -- Physiological aspects -- Health aspects, Transplantation immunology -- Research, Health care industry
Abstract

Lymph node (LN) fibroblastic reticular cells (FRCs) define LN niches and regulate lymphocyte homeostasis through producing diverse extracellular matrix (ECM) components. We examined the role of ECM laminin [alpha]4 (Lama4) using FRC-Lama4 conditional KO Pdgfrb-[Cre.sup.-/-] * [Lama4.sup.fl/fl] mice. Single-cell RNA-sequencing (scRNA-Seq) data showed the promoter gene Pdgfrb was exclusively expressed in FRCs. Depleting FRC-Lama4 reduced Tregs and dendritic cells, decreased high endothelial venules, impaired the conduit system, and downregulated T cell survival factors in LNs. FRC-Lama4 depletion impaired the homing of lymphocytes to LNs in homeostasis and after allografting. Alloantigen-specific T cells proliferated, were activated to greater degrees in LNs lacking FRC-Lama4, and were more prone to differentiate into effector phenotypes relative to the Treg phenotype. In murine cardiac transplantation, tolerogenic immunosuppression was not effective in FRC-Lama4 recipients, which produced more alloantibodies than WT. After lung transplantation, FRC-Lama4-KO mice had more severe graft rejection with fewer Tregs in their LNs. Overall, FRC-Lama4 critically contributes to a tolerogenic LN niche by supporting T cell migration, constraining T cell activation and proliferation, and promoting Treg differentiation. Hence, it serves as a therapeutic target for immunoengineering., Introduction Mammalian lymph nodes (LNs) serve as the primary initiation sites of immune responses, acting by choreographing the interactions of T cells, B cells, macrophages, and dendritic cell (DCs). The [...]

Published
2022
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33. Uromodulin to Osteopontin Ratio in Deceased Donor Urine is Associated with Kidney Graft Outcomes

Author

Mansour, Sherry G., Liu, Caroline, Jia, Yaqi, Reese, Peter P., Hall, Isaac E., El-Achkar, Tarek M., LaFavers, Kaice A., Obeid, Wassim, Rosenberg, Avi Z., Daneshpajouhnejad, Parnaz, Doshi, Mona D., Akalin, Enver, Bromberg, Jonathan S., Harhay, Meera N., Mohan, Sumit, Muthukumar, Thangamani, Schröppel, Bernd, Singh, Pooja, El-Khoury, Joe M., Weng, Francis L., Thiessen-Philbrook, Heather R., and Parikh, Chirag R.

Published
2020
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34. De-bugging the system: could antibiotics improve liver transplant outcomes?

Author

Bromberg, Jonathan S., Scalea, Joseph R., and Mongodin, Emmanuel F.

Subjects
Liver diseases -- Patient outcomes -- Drug therapy, Liver transplantation, Rifaximin, Organ transplant recipients -- Patient outcomes -- Drug therapy, Surgery, Retirement benefits, Organ transplantation, Health care industry
Abstract

Organ transplantation is now a preferred treatment for end-stage organ failure. Among the challenges for ensuring excellent clinical outcomes for transplant recipients is good initial allograft function at the time of organ implantation. This is determined in part by the functional status of the donor and donor organ, functional status of the recipient, and conduct of the operative procedure. Despite optimization of these variables, organ transplantation is still often plagued by substantial initial dysfunction, variably referred to as slow or delayed graft function, or in the most extreme cases, primary graft nonfunction necessitating urgent regrafting. In this issue of the JCI, Nakamura, Kageyama, Ito, Hirao, and colleagues investigate a potential role for the recipient's microbiome in determining graft function after liver transplantation and demonstrate the benefits of antibiotic pretreatment in both a mouse model and in human patients., Effect of the recipient's gut microbiome on liver transplantation Although many factors have been ascribed to poor initial graft function, ischemia-reperfusion injury (IRI) remains prominent among them (1). The causes [...]

Published
2019
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48. A single-dose, tolerizing vaccine induces antigen-specific regulatory T cells and durable remission while preserving healthy immunity in a mouse model of Multiple sclerosis

Author

Kapnick, Senta, primary, Gosselin, Emily A, additional, Tsai, Shannon J, additional, Oakes, Robert S, additional, Carey, Sean T, additional, Ackun-Farmmer, Marian A, additional, Froimchuk, Eugene, additional, Yanes, Alexis A, additional, Eppler, Haleigh B, additional, Noshin, Maeesha, additional, Tostanoski, Lisa H, additional, Black, Sheneil K, additional, Zeng, Xiangbin, additional, Bromberg, Jonathan S, additional, and Jewell, Christopher M, additional

Published
2023
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