Kenneth A. Newell , MD, PhD - Basic Science Research Faculty

Kenneth Newell, MD

Director, Living Donor Kidney Program
Associate Professor
Department of Surgery
Division of Kidney and Pancreas Transplantation
Emory University School of Medicine

Basic: Clinical evidence such as inferior graft survival and increased rates of rejection demonstrate that intestinal allografts are uniquely immunogeneic. Our laboratory has shown that this is at least in part due to a strong immune response mediated by CD8+ T cells. Importantly, some biologic therapies that inhibit CD4+ T cell function do not impair CD8+ T cell function to the same degree. We have therefore explored alternative strategies for inhibiting CD8+ T cell function including detailed investigation of several TNF receptor superfamily molecules including CD154, membrane lymphotoxin, 4-1BB, and LIGHT. These experiments suggest potential targets of intervening in the immune response to intestinal allografts but also provide more basic insights into the behavior of CD8+ T cells that may be applicable to other disease processes such as autoimmunity and immunity to viral infections and tumors.

Recently we have expanded our studies to include an examination of tissue specific factors that may contribute to differences in the nature of the immune response to different organs. The intestine posses a unique immunologic microenvironment which includes organized secondary lymphoid tissues, specialized immune cell populations, and unique chemokines and integrins to regulate cell trafficking. Our data demonstrate that the secondary lymphoid organs within the transplanted intestine contribute to the process of intestinal allograft rejection and may contribute to the unique immunogenicity of transplanted intestines.

In collaboration with Drs. Christian Larsen and Aron Lukacher we have undertaken studies designed to understand the immune response to polyoma BK virus (BKV) following transplantation. BKV is a common, usually asymptomatic virus that persists in the renal tubular cells of healthy individuals. Over the last decade BKV has emerged as a major pathogen leading to dysfunction and failure of transplanted kidneys. However, little is understood about the mechanisms responsible for the control of BKV following renal transplantation.  Making use of unique microsurgical models in mice and immunologic reagents available through the ETC we have submitted an R01 application to the NIH to further investigate BKV-induced nephropathy and evaluate new therapeutic approaches.

Clinical: Outcomes of transplantation have continued to improve dramatically over the last three decades. This is at least in part due to the development of more and better immunosuppressive agents. However, the long-term reliance upon drugs that globally suppress the immune system is associated with numerous deleterious side effects. For this reason, immunosuppressive drug minimization or withdrawal is now an important focus of the transplant community. Two NIH funded projects seek to address this issue. In the first funded project we are studying patients who have maintained excellent graft function despite no longer taking immunosuppressive drugs. This small cohort is recruited from around the world for the purpose of gathering patient data and clinical material to evaluate potential assays predictive of “tolerance”. The results obtained will be compared to several other groups of transplant recipients. A second set of NIH-sponsored trials is intended to develop and validate assays for the purpose of guiding decisions about immunosuppessive drug management. This project is a collaboration among investigators at the Cleveland Clinic, Case Western Reserve, the University of Manitoba, Brigham and Womens’ Hospital (Harvard), the University of California San Francisco, Yale University, and Emory University. It is comprised of a number of sub-studies aimed at developing assays to monitor both the cellular and humoral response to organ allografts and then to use these assays prospectively to manage immunosuppressive medications following kidney, heart, and lung transplantation.

A second major factor contributing to the dysfunction and premature loss of transplanted kidneys is the continued dependence upon nephrotoxic immunosuppressive drugs to prevent rejection. In an investigator-initiated single center study we will examine the potential of efalizumab, an antibody specific for LFA-1 which has been shown to be immunosuppressive and is FDA approved for the treatment of psoriasis, to replace nephrotoxic calcineurin inhibitors following transplantation. This study will also make use of new strategies to monitor the immune response following transplantation that are under development at the ETC.

Recent Publications (2007 – 2008)

  • Indefinite Survival of Intestinal Allografts in NIK Mutant Mice. Wang, J., Dong, ., Sun, J., Taylor, R., Williams, I.R., K.A. Newell. American Transplant Congress, May 7, 2007, San Francisco, CA.  
  • PD-1 Negatively Regulates CD8 T cell-mediated Mucosal Autoimmunity. V.Vezys, D. asopust, A. Sharpe, G. Freeman, K. Newell, and R. Ahmed. American Association of Immunologists Annual Meeting, April 5 – 9, 2008, San Diego, CA.  
  • A Unique B cell Signature Associated with Operational Tolerance. K.A. Newell, A. Asare, T. Gisler, M.S. Suthanthiran, W. Burlingham, W. Marks, L. Turka and V. Seyfert-Margolis. American Transplant Congress, May 31 – June 4, 2008, Toronto, Canada.  
  • TGF and Long-term Acceptance of Intestinal Allografts by aly/aly Mice. J. Wang, Y. Dong, J. Sun, I.R. Williams and K.A. Newell. American Transplant Congress, May 31 – June 4, 2008, Toronto, Canada.  
  • B Cells and Antibody Are Not Sufficient to Mediate Rejection of Intestinal llografts in Mice. Y. Dong, J. Wang, J. Sun, I.R. Williams, and K.A. Newell. American Transplant Congress, May 31 – June 4, 2008, Toronto, Canada.  
  • Laparoscopic Donor Nephrectomy: Multiple Arteries Are Not Associated with Worse Outcomes. C. Bearden, A. Agarwal, N. Turgeon, P. Tso, K. Ogan, T.C. Pearson, A.D. Kirk, C.P. Larsen and K.A. Newell. American Transplant Congress, May 31 – June 4, 2008, Toronto, Canada.  
  • Impact of Rabbit Anti-Thymocyte Globulin Induction Therapy on Reactivation of BK Virus in Renal Transplant Recipients. Agarwal, A., Meetha, A., Kokko, K.E., Turgeon, N.A., Tso, P.L., Newell, K.A., Pearson, T.C., Larsen, C.P., and A.D. Kirk. American Transplant Congress, May 31 – June 4, 2008, Toronto, Canada.