Despite continued reductions in short-term rejection rates, long-term outcomes have not significantly improved in the past decade. In the face of this the pressing unmet need, there have been no fundamentally new immunosuppressive agents that have been approved in the new millennium. Our Collaborative will investigate efalizumab as an alternative to CNI-based immunosuppression (IS) in kidney and liver transplantation. Clinical endpoints include efficacy and safety and the trial will systematically assess whether avoidance of CNI-based maintenance IS with efalizumab provides superior preservation of renal structure and function and lower rates of PTDM, hypertension, and dyslipidemia relative to a tacrolimus-based regimen. The studies will be heavily leveraged to gain mechanistic insight regarding the etiology of native renal injury and IFTA and to develop proteomic or gene expression biomarkers of progressive renal injury. We will develop clinically relevant, mechanistically based, non-invasive assays for the early detection of renal injury with the goal of translating our findings into practical tools aiding the clinician in patient care. We will acquire important data on the impact of efalizumab and tacrolimus on protective immunity by systematically defining the type and pattern of viral reactivation observed with each regimen, as well as assessing the impact on peripheral lymphocyte homeostasis and the phenotype and function of virus-specific memory T cells. We will determine whether ongoing exposure of the recipient to donor-antigens under the sustained blockade of LFA-1 with efalizumab while avoiding CNI will result in alterations in anti-donor T cell and/or humoral immunity or an Increased Incidence of recently described tolerance signatures. Given the prevalence of renal injury (native and allograft) and centrality of immune function across all transplant settings regardless of IS regimen, we anticipate broad applicability of these goals. We have aligned three high volume transplant hospitals with extensive experience in clinical transplant studies and recruited investigators with substantial, published experience in human transplant immunobiology to insure that our studies will yield clinically meaningful and mechanistically important results.

Public Health Relevance

Despite reductions in short-term rejection rates, long-term outcomes have not significantly improved in the past decade and there have been no fundamentally new immunosuppressive agents that have been approved in the new millennium. Our Collaborative will investigate efalizumab as an alternative to CNI-based immunosuppression in kidney and liver transplantation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI084150-03
Application #
8137832
Study Section
Special Emphasis Panel (ZAI1-SV-I (M1))
Program Officer
Hayes, Deborah
Project Start
2009-09-25
Project End
2014-08-31
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
3
Fiscal Year
2011
Total Cost
$2,019,903
Indirect Cost
Name
Emory University
Department
Surgery
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Newell, K A; Mehta, A K; Larsen, C P et al. (2017) Lessons Learned: Early Termination of a Randomized Trial of Calcineurin Inhibitor and Corticosteroid Avoidance Using Belatacept. Am J Transplant 17:2712-2719
Anderson, D J; Lo, D J; Leopardi, F et al. (2016) Anti-Leukocyte Function-Associated Antigen 1 Therapy in a Nonhuman Primate Renal Transplant Model of Costimulation Blockade-Resistant Rejection. Am J Transplant 16:1456-64
Ong, Song; Mannon, Roslyn B (2015) Genomic and proteomic fingerprints of acute rejection in peripheral blood and urine. Transplant Rev (Orlando) 29:60-7
James, Alexandra; Mannon, Roslyn B (2015) The Cost of Transplant Immunosuppressant Therapy: Is This Sustainable? Curr Transplant Rep 2:113-121
Rychert, Jenna; Danziger-Isakov, Lara; Yen-Lieberman, Belinda et al. (2014) Multicenter comparison of laboratory performance in cytomegalovirus and Epstein-Barr virus viral load testing using international standards. Clin Transplant 28:1416-23
Mannon, Roslyn B (2012) Macrophages: contributors to allograft dysfunction, repair, or innocent bystanders? Curr Opin Organ Transplant 17:20-5
Randhawa, Parmjeet; Mannon, Roslyn B (2012) A case of late kidney allograft failure: a clinical pathological conference from American Society of Nephrology Kidney Week 2011. Clin J Am Soc Nephrol 7:1884-9
Cravedi, Paolo; Maggiore, Umberto; Mannon, Roslyn B (2010) Low-density array PCR analysis of reperfusion biopsies: an adjunct to histological analysis. Nephrol Dial Transplant 25:4077-86