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Yale | Cardiovascular Medicine | Faculty   Daniel R. Goldstein, M.D. Assistant Professor of Medicine M.D., St. George's Hospital Medical School, London, England 1992; Residency in Internal Medicine, Johns Hopkins Bayview Medical Center, Johns Hopkins University School of Medicine, Baltimore, MD 1993-1996; Cardiology Fellowship, Cardiovascular Diseases Training, University of Alabama at Birmingham 1996-2000; Transplant Immunology Training, University of Alabama at Birmingham 1997-1999; Cardiac Transplantation Training, University of Alabama at Birmingham 2000-2001; joined Yale Faculty, 2001. Research Interests My laboratory has two main research interests: The role of innate immunity in transplantation The impact of aging on inflammation and immunity. The role of innate immunity in transplantation My initial research efforts were on the role of Toll-like receptors (TLRs, key cellular mediators of innate immunity) in transplant rejection responses. My laboratory was the first to demonstrate that TLRs were critical for acute allograft rejection in a murine, minor mismatch skin transplant model (Journal of Clinical Investigation 111: 1571-1578, 2003). In this paper, we found that MyD88 (a critical TLR signal adaptor protein) was essential for dendritic cell (DC) maturation and priming of Th1 immune responses after transplantation. Given that infections are not known to drive transplant rejection in this model, this paper was one of the first to determine that TLR signaling via MyD88 is critical for a non-infectious inflammatory insult. We subsequently demonstrated an important role for TLRs in Th1 alloimmune responses in more immunogenic skin and cardiac murine experimental transplant models (American Journal of Transplantation 4: 1429-1439, 2004). This work was the basis for my first successful R01 application, which investigates the role of innate immunity in transplantation tolerance (R01AI064660). With this funding, my laboratory then went on to demonstrate that MyD88 signaling impeded the induction of transplantation tolerance (Journal of Immunology 177: 5307-5316 2006). Furthermore, my laboratory has investigated the innate activators of DCs during acute allograft rejection and found that fragments of the extracellular matrix, hyaluronan, activated DCs to prime allogeneic T cells in a TLR-dependent manner (American Journal of Transplantation, 6: 2622-2635, 2006). In this paper, we also reported that human lung transplant patients who were diagnosed with chronic rejection manifested higher hyaluronan levels than those free of this disease. This work was funded in part by a faculty development grant from the American Society of Transplantation. Finally, we examined the role of TLR signaling in neonates and whether altered TLR responses might explain the ease by which neonates can be induced to accept allografts. My laboratory reported that TLR activated murine neonatal B cells possess unique immunoregulatory properties that impair Th1 alloimmune responses (Journal of Immunology, 179: 1700-1710, 2007). This work was supported by the Roche Organ Transplant Research Foundation. Hence, I have been one of the first investigators to provide fundamental information regarding the role of innate immunity, specifically TLR signaling, in transplant responses. The practical implications of this work are that various groups are now considering transiently inhibiting TLR responses during the initial period after organ implantation. My laboratories future plans are to investigate the molecular mechanisms by which inflammation impacts transplantation tolerance. Aging and immune function During the last four years, I have developed a new line of investigation: the role of aging in immune responses. My interest was initially fueled by the question of whether impaired innate immune responses with aging explain the reduced ability of older transplant recipients to reject allografts. However, I quickly became interested in broader medical issues, specifically how aging impairs host defense to viral infections and how to boost defective immune responses with aging. After initially receiving pilot funds from the Hartford Foundation and Pepper Center, I successfully competed for the prestigious Beeson Award, which I received in 2005. This proposal examines T cell biology during viral infection with aging and allowed my laboratory to develop expertise in viral infectious models and in vitro cell culture techniques. My laboratory subsequently demonstrated that myeloid DCs, the most potent antigen presenting cells (APCs), manifested preserved TLR immune responses with aging and that defective priming of CD8+ T cells with aging during viral infection was intrinsic to the T cell (Aging Cell, 5: 473-486, 2006). This work led to the successful acquisition of a second R01 in 2007 (R01AG028082) to further investigate how aging modifies innate DC responses and adaptive T cell responses during viral infections. Importantly, this award investigates whether TLR-based vaccines can restore defective immune responses in aged hosts. Future plans My laboratory will investigate further how aging impacts innate and adaptive immune responses to viral infections. We also have an interest to examine how aging modifies inflammation and how this may impact vascular diseases. I received pilot funds from the Society of Geriatric Cardiology to initiate a program in this area. Clinical Interests Cardiac transplantation and heart failure Peer-Reviewed Original Research George JF, Sweeney SD, Kirklin JK, Simpson EM, Goldstein DR, Thomas JM. An essential role for Fas ligand in transplantation tolerance induced by donor bone marrow. Nature  Medicine. 1998, (4):333-5.. Goldstein DR, Chang T, Sweeney SD, Kirklin JK, Thomas JM, George JF. Enhanced allograft survival induced by post-transplant donor spleen cell infusion occurs via a mechanism that is distinct from the mechanism of enhancement by donor bone marrow. Transplantation 2000, (5):1020-1022. Goldstein DR, Chang T, Sweeney SD, Kirklin JK, Thomas JM, George JF. A differential requirement for CD8+ donor cells in the augmentation of allograft survival by posttransplantation administration of donor spleen cells and donor bone marrow cells. Transplantation 2000, (7): 1068-1073. Goldstein DR, Thomas JM, Kirklin JK, George JF.  The Role of Natural Killer Cells in Augmentation of Allograft Survival by Donor Spleen and Bone Marrow Cells. Transplantation 2001, (5): 954-6. Goldstein DR, Thomas JM, Kirklin JK, George JF. Indefinite allograft survival mediated by donor bone marrow is dependent on the presence of a functional Fas gene in the recipients. Journal of Heart and Lung Transplantation 2001, (10): 1132-5. Goldstein DR, Coffey CS, Benza RL, Nanda NC, Bourge RC. Relative Postoperative bradycardia does not lead to adverse outcomes after cardiac transplantation. American Journal Transplantation 2003,  (4): 484-491. Goldstein DR, Tesar BM, Akira S, Lakkis FG. Critical Role of Toll-Like Receptor Signal Adaptor Protein MyD88 in Acute Allograft Rejection. Journal of Clinical Investigation 2003, (111): 1571-1578. Tesar BM, Zhang J, Li Q, Goldstein DR. TH1 Immune Responses to Fully MHC Mismatched Allografts are diminished in the absence of MyD88, a Toll Like Receptor Signal Adaptor Protein.  American Journal of Transplantation 2004, (4):1429-1439. Tesar BM, Chalasani G, Smith-Diggs L, Baddoura FK, Lakkis FG, Goldstein DR. Direct antigen presentation by a xenograft induces immunity independently of secondary lymphoid organs. Journal of Immunology 2004. (173): 437-4386. Askenase PW, Itakura A, Leite-de-Moraes MC, Lisbonne M, Roongapinun S, Goldstein DR, Szcepanik M. TLR-Dependent IL-4 production by invariant Vα14+Jα18+ NKT cells to initiate contact sensitivity in vivo. The Journal of Immunology 2005 (10): 6390-401. Jiang D, Liang J, Fan J, Yu S, Chen S, Luo Y, Prestwich GD, Mascarenhas MM, Garg HG, Quinn DA, Homer RJ, Goldstein DR, Bucala R, Lee PJ, Medzhitov R, and Noble. PW Regulation of lung injury and repair by Toll-like receptors and hyaluronan.  Nature Medicine 2005 (11): 1173-9. Tesar BM, Walker WE, Unternaehrer J, Joshi NS, Chandele A, Haynes L, Kaech S, and Goldstein DR. Murine Myeloid Dendritic Cell Dependent Toll Like Receptor Immunity is preserved with Aging. Aging Cell 2006 (5) 473-486 Walker WE, Nasr IW, Camirand G, Tesar BM, Booth CJ, Goldstein DR. Absence of Innate MyD88 Signaling Promotes Inducible Allograft Acceptance. The Journal of Immunology 2006 (177):5307-5316. Tesar B, Jiang D, Liang J, Palmer S, Noble P, Goldstein DR. The role of hyaluronan degradation products as innate alloimmune agonists. American Journal of Transplantation 2006 (6) 2622-26356 Tesar B and Goldstein DR Acute allograft rejection occurs independently of HSP-70. Transplantation 2007 (11) 1513-17 Walker WE and Goldstein DR Neonatal B Cells Suppress Innate Toll-Like Receptor Immune Responses and Modulate Alloimmunity. The Journal of Immunology 2007, (3) 1700-1710 Griffith JW, O’Connon C, Benard K, Town T, Goldstein DR, Bucula R. Innate Immune responses Mediated by TLR9 and MyD88 Regulate Susceptibility to Murine Cerebral Malara. Journal of Infectious Diseases 2007 196:1553-64 Editorials, Reviews, Chapters, Books Goldstein DR. Reflections from the other side of the pond. Essay. British Medical Journal 1995 (310): 745-6. Essay. Goldstein DR. Toll Like receptors and other links between innate and acquired alloimmunity. Current Opinions in Immunology 2004 (16): 534-544. Review. Goldstein DR and Palmer SM. Role of Innate Immunity in Thoracic Organ Transplantation. Journal of Heart and Lung Transplantation 2005 (11): 1721-9. Review. Goldstein DR, Bose A, Lakkis FG, Mechanisms of Renal Allograft rejection. Principles of Molecular Medicine, 2006. 2nd Edition, Humana Press. Book Chapter. Obhrai J and Goldstein DR. Role of Toll Like Receptors in solid organ transplantation. Transplantation 2006 81(4):497-502. Review. Goldstein DR. Toll like receptors and acute allograft rejection. Transplant            Immunology 2006 17: 11-5. Review Walker WE and Goldstein DR. TLR pathways and Innate responses to allografts.            Current Opinions in Organ Transplantation. 2007 (12): 5-9. Review Shen H and Goldstein DR. Role of TLRs in Transplantation Tolerance. Expert Review in Clinical Immunology. 2007 (3): 136-144. Review Tesar B and Goldstein DR. Toll like receptors and their role in transplantation. Frontiers in Bioscience 2007 in press Goldstein DR. The identity of innate immune activators in organ transplantation: origins from within or exterior to the host? American Journal of Transplantation 2007 (7) 1692-1694. Shirali AC and Goldstein DR. Activation of the innate immune system by the endogenous ligand hyaluronan. Current Opinions in Organ Transplantation 2008 13: 20-25. Shirali AC and Goldstein DR. The Toll of Kidney Diseases. Invited Review. The Journal of the American Society of Nephrology. In press Copyright © 2000, Yale University, New Haven, Connecticut, USA. All rights reserved. Comments or suggestions to site editor. Certifying authority: Last modified:Wednesday, 09-Apr-2008 12:50:16 EDT (PL).