We are primarily interested in how inflammation impacts organ transplantation, and how aging alters acute and chronic inflammation to enhance disease.
Extensive Research Description
As a transplant physician, I have investigated the mechanisms and consequences of innate immune activation after organ transplantation. My laboratory was the first to demonstrate that Toll like receptor signaling via MyD88 accelerated the tempo of acute transplant rejection (JCI, 2003, AJT, 2004) and impaired transplant tolerance (JI, 2006, JASN, 2008). These were some of the first studies to show that Toll like receptors activate inflammation in sterile in vivo models. The activators of the innate immune system after transplantation have remained elusive. We recently discovered that haptoglobin stimulates innate immunity to induce inflammation after organ transplantation (JCI, 2012). As a result of our work some laboratories and pharmaceutical companies are targeting innate immune pathways to reduce inflammation after organ transplantation.
I am also interested in how aging impacts immunity, initially to determine if older transplant recipients exhibit altered immune responses to transplantation. My laboratory challenged the paradigm that declining immune function is responsible for age-associated disorders. In murine viral infection models, we determined that exaggerated IL-17 production by NKT cells induces lethal immune pathology (Cell Host and Microbe, 2009). In murine vascular models, we demonstrated that elevatedinflammatory responses by vascular smooth muscle cells may predispose to atherosclerosis (ATVB, 2012). Finally, in murine transplant models we documented that enhanced responses by naïve CD8+ T cells may impair immune tolerance with aging (JI, 2011). In sum, we have made innovative findings, challenging current paradigms, that elevated immune responses explain age-associated phenotypes.
1) Organ Transplantation
- How inflammation impacts organ transplantation
- Identifying inflammatory triggers that induce acute organ transplant rejection in experimental skin and heart transplant using non-biased approaches such as proteomics. The impact of this work is that it may identify novel targets to reduce intra-graft inflammation to improve outcomes after organ transplantation.
- Employing nanoparticles to enhance allograft survival in experimental skin and heart transplant models. The impact of this work is that is may elucidate a novel platform to deliver immune suppressants to organ transplant recipients and avoid the side-effects of these medications.
- How aging impacts immune regulation to organ transplants. We are employing experimental models of organ transplant to elucidate novel age-specific pathways by which aging impacts the immune response to organ transplantation. The impact of this work is that it may reveal novel therapeutics to improve the efficacy of organ transplantation to older recipients, the largest pool of patients that are receiving organ transplants.
2) Aging and Inflammation
- How aging impacts the acute innate immune response to primary influenza viral infection. The impact of this work is that it may reveal novel pathways and hence therapies by which aging leads to morbidity and mortality after influenza viral lung infection.
- How aging impacts chronic inflammation to enhance atherosclerosis. We are employing murine experimental models to understand how aging leads to enhanced atherosclerosis. The impact of this work is that it may lead to novel therapies to reduce the impact of atherosclerosis with aging.
- Song Y, Shen H, Du W and Goldstein DR. Inhibition of x-box binding protein 1 expression reduces tunicamycin-induced apoptosis in aged murine macrophages. Aging Cell 2013 (12): 794-801
- Song Y, Shen H, Schenten D, Lee PJ and Goldstein DR. Aging enhances the basal production of IL-6 and CCL2 in vascular smooth muscle cells. Arteriosclerosis, Thrombosis and Vascular Biology, 2012 Jan;32(1):103-9
- Shen H, Song Y, Colangelo C, Wu T, Bruce C, Scabia G, Maffei M and Goldstein DR. Haptoglobin activates innate immunity to enhance acute transplant rejection in mice The Journal of Clinical Investigation 2012, (122):383-387
- Leng J, Stout-Delgado HW, Kavita U, Jacobs A, Tang J, Du W, Tussey L, Goldstein DR.Efficacy of a vaccine that links viral epitopes to flagellin in protecting aged mice from influenza viral infection.Vaccine 2011 (29): 8147-8155
- Shirali AC, Look M, Du W, Kassis E, Stout-Delgado HW, Fahmy TM, Goldstein DR. Nanoparticle Delivery of Mycophenolic Acid Upregulates PD-L1 on Dendritic Cells to Prolong Murine Allograft Survival.Am J Transplant. 2011 (12): 2582-92.
- Du W, Shen H, Galan A, Goldstein DR.An Age-Specific CD8+ T Cell Pathway That Impairs the Effectiveness of Strategies To Prolong Allograft Survival.J Immunol. 2011 Oct 1;187(7):3631-40.
- Stout-Delgado HW, Tesar BM, Walker WE, Shen H and Goldstein DR. Aging promotes neutrophil-induced mortality by augmenting IL-17 production during viral infection. Cell Host and Microbe (Cell Press) 2009 (6) 446-456, *Featured article with accompanying edi
- Walker WE, Booth CJ and Goldstein DR. TLR9 and IRF3 cooperate to induce a systemic inflammatory response in mice injected with liposome:DNA. Molecular Therapy (Nature Publishing Group) 2009 (4): 775-85 *Highlighted “In This Issue”
- Shen H and Goldstein DR. IL-6 and TNFa synergistically inhibit allograft acceptance. The Journal of the American Society of Nephrology 2009 (5) 1032-40 *Selected for Faculty of 1000, Medicine
- 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
- Stout-Delgado HW. Yang X, Walker WE, Tesar BM and Goldstein DR. Aging impairs the upregulation of IRF-7 in plasmacytoid DCs during TLR9 activation. The Journal of Immunology 2008 (181): 6747-6756 *Highlighted “In This Issue”
- 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.