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Todd Grazia, MD

Associate Professor of Medicine and Immunology


Dr. Grazia is board certified in Internal Medicine, Pulmonary Medicine, and Critical Care Medicine.  He is a UNOS certification-eligible lung transplant physician. His clinical interests include lung transplantation, end-stage lung disease, and pulmonary vascular disease/right ventricular failure. He has a specific clinical research interest in the attenuation of acute and chronic lung and heart allograft rejection via immune-modulatory therapies, including the potential use of stem cell/progenitor cell therapy. In terms of basic science research, Dr. Grazia is focused primarily on understanding the interface between the donor vasculature and the host immune response as it relates to acute rejection and ultimately to its relationship to the development of maladaptive fibrosis (chronic rejection) in cardiothoracic solid organ transplantation.  Dr. Grazia's lab works in close collaboration with Dr. Gill, Dr. Zamora, and Dr. Pietra. Dr. Grazia is currently funded by the NIH, AHA, and JDRF.

Office Phone: 303.724.6822
Email: todd.grazia@ucdenver.edu

Laboratory Personnel - Helen Lepper, BS, Professional Research Assistant (click on name for more information)

Grazia Lab Selected Publications:

  1. CD4 T-cells Mediate Cardiac Xenograft Rejection via Host MHC II. Plenter RJ, Grazia TJ, Doan AN, Gill RG, and Pietra BA. J Heart Lung Transplant. 2012 Jul 10. [Epub ahead of print]PMID:22789136
  2. Prolongation of Cardiac Allograft Survival by a Novel Population of Autologous CD117+ Bone Marrow-Derived Progenitor Cells.
  3. Grazia TJ, Plenter RJ, Lepper HM, Victorino F, Miyamoto SD, Crossno JT Jr.,  Pietra BA, Gill RG, and Zamora MR.
    Am J Transplant. 2011 Jan;11(1):34-44. doi: 10.1111/j.1600
      
  4. Grazia TJ, Plenter RJ, Lepper HM, Victorino F, Miyamoto SD, Crossno, JT Jr, Pietra BA, Gill RG, and Zamora MR. Prolongation of Cardiac Allograft Survival by a Novel Population of Autologous CD117+ Bone Marrow-Derived Progenitor Cells. Under Revision for Am J Transplant. June 2010
  5. Grazia TJ, Plenter RJ, Weber SM, Lepper HM, Victorino F, Zamora MR, Pietra BA, Gill RG. Acute cardiac allograft rejection by directly cytotoxic CD4 T cells: parallel requirements for Fas and perforin. Transplantation. 2010 Jan 15;89(1):33-9. PubMed PMID: 20061916.
  6. Levi ME, Quan D, Ho JT, Kleinschmidt-Demasters BK, Tyler KL, Grazia TJ. Impact of rituximab-associated B-cell defects on West Nile virus meningoencephalitis in solid organ transplant recipients. Clin Transplant. 2010 Mar 1;24(2):223-8. Epub 2009 Aug 3. PubMed PMID: 19659514; PubMed Central PMCID: PMC2873850.
  7. Grazia TJ, Plenter RJ, Doan AN, Kelly BP, Weber SM, Kurche JS, Cushing SO, Gill RG, Pietra BA. Spontaneous allograft tolerance in B7-deficient mice independent of preexisting endogenous CD4+CD25+ regulatory T-cells. Transplantation. 2007 Jun 15;83(11):1449-58. PubMed PMID: 17565318.
  8. Crossno JT Jr, Majka SM, Grazia T, Gill RG, Klemm DJ. Rosiglitazone promotes development of a novel adipocyte population from bone marrow-derived circulating progenitor cells. J Clin Invest. 2006 Dec;116(12):3220-8. PubMed PMID: 17143331; PubMed Central PMCID: PMC1679707.
  9. Grazia TJ, Gill RG, Gelhaus HC Jr, Doan AN, Sleater ML, Pietra BA. Perturbation of leukocyte function-associated antigen-1/intercellular adhesion molecule-1 results in differential outcomes in cardiac vs islet allograft survival. J Heart Lung Transplant. 2005 Sep;24(9):1410-4. PubMed PMID: 16143264.
  10. Zamora MR, Nicolls MR, Hodges TN, Marquesen J, Astor T, Grazia T, Weill D. Following universal prophylaxis with intravenous ganciclovir and cytomegalovirus immune globulin, valganciclovir is safe and effective for prevention of CMV infection following lung transplantation. Am J Transplant. 2004 Oct;4(10):1635-42. PubMed PMID: 15367218.
  11. Grazia TJ, Pietra BA, Johnson ZA, Kelly BP, Plenter RJ, Gill RG. A two-step model of acute CD4 T-cell mediated cardiac allograft rejection. J Immunol. 2004 Jun 15;172(12):7451-8. PubMed PMID: 15187123.
  12. Grazia TJ, Hodges TN, Cleveland JC Jr, Sheridan BC, Zamora MR. Lobar torsion complicating bilateral lung transplantation. J Heart Lung Transplant. 2003 Jan;22(1):102-6. PubMed PMID: 12531421.
  13. Zoeller RA, Grazia TJ, LaCamera P, Park J, Gaposchkin DP, Farber HW. Increasing plasmalogen levels protects human endothelial cells during hypoxia. Am J Physiol Heart Circ Physiol. 2002 Aug;283(2):H671-9. PubMed PMID: 12124215.

Faculty Appointment: Associate Professor of Medicine and Immunology

Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, Integrated Department of Immunology, and Colorado Center for Transplantation Care Research and Education (CCTCARE)

Undergraduate Education: The University of Connecticut, B.S. Biology and Anthropology, Magna Cum Laude, Phi Beta Kappa

Medical Education: The Chicago Medical School

Residency: Boston University Medical Center

Pulmonary/Critical Care Fellowship: University of Colorado Health Sciences Center
Lung Transplantation Sub-Fellowship: University of Colorado HSC

Specifically, Dr. Grazia's lab is interested in defining the role of the micro-vasculature in the immune response of primarily vascularized thoracic and cardio-thoracic allografts. The lab has been working out the role of the endothelial cell (EC) as a potential antigen presenting cell (APC) and/or a target of the cellular immune. Thus far, they have demonstrated that the required effector T-cell (CD4+) requires MHC II expression on donor hematopoietic cells that act as APCs and that the allograft EC is the required MHC II-restricted target of the response. The lab has also elucidated the in vivo requirements for effector CD4+ T-cell killing. Specifically, they have demonstrated that the effector CD4+ T-cell requires concomitant T-cell perforin and target cell Fas expression for in vivo killing. This is the first time that a CD4+ T-cell has been demonstrated to require a cytolytic phenotype to kill in an in vivo model of solid organ transplantation.

Based on the above results, Dr. Grazia's group has identified a potential mechanism to explain the theoretical protective effect of recipient endothelial chimerism in solid organ transplant patients. Specifically, if donor endothelial cells are targets of effector T-cells, increasing the number of non-antigenic (host-derived) endothelial cells will decrease the number of targets available.  Recently, Dr. Grazia's lab has utilized an autologous progenitor cell population (defined by CD117 surface expression) to attempt to abrogate acute cardiac rejection by increasing recipient EC chimerism (via progenitor cells incorporating into damaged donor allograft blood vessels and differentiating into recipient-type ECs). While this therapy did not lead to increased recipient vascular chimerism, it did lead to robust prolongation of allograft survival (as much as 5 times that of controls). The lab is currently busy working to define the mechanism of allograft prolongation seen with this autologous progenitor cell population. These results may lead to novel clinically relevant therapeutics in the relative near future.