The Gabrielle Rich Center for Transplantation Biology Research
Yair Reisner, Director
The Henry H. Drake Professorial Chair of Immunology
The center supports the research of Prof. Tsvee Lapidot, Prof. Dov Zipori and Prof. Yair Reisner, dedicated to hematopoietic stem cell transplantation.
Highlights of these studies last year were as follows:
Prof. Tsvee Lapidot
To obtain the healthy stem cells for transplantation - either from a healthy donor or from the patient himself before or during treatment with chemotherapy - these cells must be "encouraged" to come out of the marrow into the bloodstream (in other words, they must be "mobilized"). To understand how this happens, we probed the turn of events in the bone marrow and found that stem cells in the marrow are freed into the blood via an "anchors aweigh" mechanism. The findings put a key protein into focus - SDF-1. This protein had previously been found by this and other research teams worldwide to anchor stem cells inside the marrow by activating adhesion molecules (molecules that serve as "glue"). We now have found that SDF-1 must be degraded for stem cell mobilization to take place and uncovered the underlying degradation mechanism. This finding which was published this year in the prestigious journal Nature Immunology, Is not only important for the understanding of the biology of stem cell transplantation but it may also lead to improved collection of stem cells for clinical transplantations.
Prof. Dov Zipori
Our studies on the interactions between hemopoietic cells and the organ me senchymal stroma indicate that transforming growth factor (TGF)β cytokines are involved in the formation of restrictive microenvironments. Activin A, one member of the TGFβ family, was initially found to cause apoptotic death of tumor B lineage cells. We have now found that activin A specifically restrains the differentiation of normal precursor B cells: activin A caused accumulation of B lineage cells at early stages of differentiation both in vivo and in vitro. This restrictive activity is not exerted on other hemopoietic lineages. The expression of such lineage specific restrictive molecules may assure the control of adult pluripotent stem cells, which occur in multiple organs and tissue types, to prevent their differentiation into directions that may endanger the integrity of the tissue.
Prof. Yair Reisner
Clinical studies continue with the implementation of our new approach, making use of 'mega dose ' stem cell transplants , which enables the use of mismatched family members. Although we have adequately shown the efficacy of this approach in more than 300 patients, it must be analyzed properly, the same as for any new drug by formal multi-center clinical trials in Europe and in the USA, and we are presently in the middle of this important final step.
This month we are happy to launch a web site which will serve as a quarterly bulletin, showing update of clinical and scientific data for the benefit of patients and doctors who might be interested in our approach. The site address is: http://www.haplo.org/index.php
In addition, we are focusing our efforts on a new application of stem cell transplantation for patients with diseases that could be cured by transplantation but who are not at immediate risk from their disease and, therefore, should not be exposed to the current risky protocols. Thus, the challenge is how to overcome graft rejection following mild radiation or chemotherapy based protocols. To that end, based on encouraging results in the mouse model, we are currently developing new cell preparations which could be given in conjunction with the stem cells in order to facilitate engraftment of the latter cells under such safe conditions.