Daniel Robert Goldstein MBBS

Associate Professor of Medicine (Cardiology) and of Immunobiology

Research Interests

immunity in transplantation; impact of aging on inflammation and immunity

Current Projects

Investigation of the molecular mechanisms by which inflammation impacts transplantation tolerance; further investigation of how aging impacts innate and adaptive immune responses to viral infections, examination of how aging modifies inflammation and how this may impact vascular diseases; have received pilot funds from the Society of Geriatric Cardiology to initiate a program in this area

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Research Summary

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). 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. 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). 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.

Extensive Research Description

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. 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.

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Selected Publications