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Bypassing Immune Rejection in Stem-Cell-Based Therapies, Stanford University Study



8/16/2013 9:49:04 AM

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Durham, NC – The scientific community has held tremendous hope for the eventual emergence of stem cell transplantation as a broadly applicable and highly effective therapeutic strategy. However, the realization of this hope has been plagued by the indomitable immune response to the transplantation of human embryonic stem cell (hESC) derivatives, which prevents the engraftment and long-term survival necessary for functional recovery or preservation of the host tissue.

In an article featured in the latest issue of STEM CELLS, a research group from Stanford University describes a novel regimen for quashing this immunologic barrier — a short-course treatment with two costimlation-adhesion blockade agents, allowing engraftment of transplanted differentiated stem cells and their prolonged survival in tissue.

"Inducing immune tolerance to human embryonic stem cell graft is critical for the clinical success of regenerative medicine,” commented Dr. Joseph Wu, M.D., Professor of Medicine and Radiology at the Stanford University School of Medicine. “We have realized, however, that traditional immunosuppressive therapies used to prevent solid organ rejection, such as calcineurin inhibitors and corticosteroids, are insufficient to prevent human embryonic stem cell rejection following transplantation.”

In the study, hESCs were made to express enhanced green fluorescent protein (eGFP), differentiated to endothelial cells and cardiomyocytes, and transplanted into mouse hindlimbs as well as into both healthy and ischemic mouse myocardia. A novel costimulation-adhesion blockade method was then used alongside a more traditional therapy involving cyclosporine to induce immunosuppression. Detection of eGFP in the tissues allowed the team to track the engraftment and longevity of the transplanted cells over time. The costimulation-adhesion method yielded vastly superior results to the cyclosporine treatment, not only showing significantly improved engraftment and survival of the cells in the tissues but ultimately showing the effective preservation of cardiac function following stem cell transplantation in an induced myocardial infarction model, as shown through MRI.

“Here we demonstrate that a short-course, dual-agent regimen that prevents optimal T cell activation is sufficient to promote the robust and long-term survival of embryonic stem cell derivatives in both healthy and injured tissues in mouse models,” Dr. Wu explained. The authors indicate that the superior response of the transplanted cells to the costimulation-adhesion therapy may be attributed to its repression of both adaptive and innate immunity, which is likely to aid in mitigating the tissues’ rejection of these characteristically immunogenic cells. The researchers’ method led to both local and systemic upregulation of T cell immunoglobulin and mucin domain 3 (TIM3), a Th-1-specific cell surface protein, in addition to an overall reduction of pro-inflammatory cytokines.

“Application of hESC and iPSC-derived cells holds great promise for cell replacement therapies in man, with clinical trials already ongoing in USA/Europe and soon in Japan,” noted Majlinda Lako, Ph.D., Associate Editor for STEM CELLS and Professor of Stem Cell Science at the Institute of Genetic Medicine, Newcastle University. “This current study brings us a step closer to overcoming immunological barriers that have hampered these clinical promises and addresses important issues that must be tackled before successful realization of pluripotent stem cell therapies can take place in humans.”

Speaking on behalf of his research team, Dr. Wu stated, “We are excited by these findings and about their implications for the field. This work demonstrates a simple, effective approach to overcome the immunologic barrier of using human embryonic stem cell derivatives that is far superior to conventional agents currently in use clinically."

About the Journal: STEM CELLS, a peer reviewed journal published monthly, provides a forum for prompt publication of original investigative papers and concise reviews. The journal covers all aspects of stem cells: embryonic stem cells/induced pluripotent stem cells; tissue-specific stem cells; cancer stem cells; the stem cell niche; stem cell epigenetics, genomics and proteomics; and translational and clinical research. STEM CELLS is co-published by AlphaMed Press and Wiley-Blackwell.

About AlphaMed Press: Established in 1983, AlphaMed Press with offices in Durham, NC, San Francisco, CA, and Belfast, Northern Ireland, publishes three internationally renowned peer-reviewed journals with globally recognized editorial boards dedicated to advancing knowledge and education in their focused disciplines. . STEM CELLS® (www.StemCells.com), now in its 31st year, is the world's first journal devoted to this fast paced field of research. The Oncologist® (www.TheOncologist.com), in its 18th year, is devoted to community and hospital-based oncologists and physicians entrusted with cancer patient care. STEM CELLS TRANSLATIONAL MEDICINE® (www.StemCellsTM.com), in its second year, is dedicated to significantly advancing the clinical utilization of stem cell molecular and cellular biology. By bridging stem cell research and clinical trials, SCTM will help move applications of these critical investigations closer to accepted best practices.

About Wiley-Blackwell: Wiley-Blackwell is the international scientific, technical, medical, and scholarly publishing business of John Wiley & Sons, with strengths in every major academic and professional field and partnerships with many of the world’s leading societies. Wiley-Blackwell publishes nearly 1,500 peer-reviewed journals and 1,500+ new books annually in print and online, as well as databases, major reference works and laboratory protocols. For more information, please visit www.wileyblackwell.com or our new online platform, Wiley Online Library (wileyonlinelibrary.com), one of the world’s most extensive multidisciplinary collections of online resources, covering life, health, social and physical sciences, and humanities.

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