|Professor Yair Reisner, Department Head
The Henry H. Drake Professor of Immunology
Location: Wolfson Bldg., Room 014
Our research has been involved, for more than twenty years, with the subject of transplantation immunology and, more specifically, with questions relating to stem cell transplantation. Two major milestones, namely transplantation of mismatched hematopoietic lectin separated stem cells in SCID patients (1), and, latterly, the use of ‘mega dose’ transplants in leukemia patients (2), have already been translated into clinical achievements. Another one, published initially in Nature Medicine in 2003 (3), could potentially pave the way for the use of embryonic committed stem cells as a new source for organ transplantation (4). The feasibility of this new approach, which offers reduced immunogenicity in xenotransplantation, has been shown for porcine kidney (3), liver (5,6), heart (5), lung (5), spleen (7) and pancreas (5, 8). The latter is already in advanced preclinical primate studies, suggesting potential cure of diabetes. In parallel to the major drive to improve outcome of transplants, a major basic subject of our studies addresses mechanisms of tolerance induction by progenitor cells in the bone marrow and by other tolerizing cells (9, 1).
Taken together, our research continues to focus on two major lines of investigation:
1) Tolerance induction by mis-matched hematopoietic stem cells and other tolerizing cells
We have emphasized in recent years the role of accessory tolerizing cells, which could enable to reduce the toxicity of the conditioning, so as to apply this approach in the context of organ transplantation or as a prelude for cell therapy in cancer by donor lymphocyte infusions. In particular, we studied extensively the role and the mechanism of action of veto cells. This major drive, supported by two NIH and two EC grants, has led to the development of new veto cell preparation depleted of GVH reactivity (10, 11), as well as to new insights on mechanisms underlining the tolerance induced by CD34 stem cells (12, 13) as opposed to CD8+ veto CTLs (14, 15, 16). Our original finding that CD34 stem cells and their immediate progeny, namely, early myeloid CD33 cells, exhibit veto reactivity (12), could explain in part how mega dose CD34 stem cells overcome rejection in mis-matched leukemic patients. We showed that deletion of ant-donor effectors is mediated through TNFα (13) while in tolerance induction by veto CTLs, Fas-FasL mechanism is more relevant (15, 16). CD8 molecules on the veto CTLs interacting with H2-Class 1 on the effector cells were previously demonstrated to be also important, but only very recently we found a link between the two pathways, showing that the latter interaction leads to ERK phosphorilation which in turn induces down regulation of the apoptosis inhibitor XIAP . A new development of the veto concept was recently suggested by our studies when we demonstrated that human anti-3rd party veto CTLs could eradicate B cell malignancies via a TCR independent killing (17). New insights on the mechanism of action again suggest a role for the CD8-MHC class 1 interaction.
In parallel to the mechanistic studies, we demonstrated synergy of veto CTLs with Treg cells (18) and advocated the role of "off-the shelf" third party Treg cells regardless of their TCR specificity (19). In collaboration with MD Anderson we started this year an NIH sponsored clinical study of veto CTLs in patients receiving purified CD34 cells under reduced intensity conditioning.
2) Committed embryonic tissue as a new source for organ transplantation
In 2003, we were able to define for the first time, using metanephroi as a proof of principal, an optimal gestational ‘window’ required for successful organogenesis of human and porcine kidneys (3). More recent results suggest that by using the same approach, “window” transplants can be defined successfully for embryonic pig liver (5,6), heart (5), lung (5), spleen (7) and pancreas (5, 8). Furthermore, we demonstrated that embryonic pig pancreatic tissue harvested at E42 can grow and develop in fully competent mice under mild immune suppression and can cure diabetic mice (8). Gene analysis comparing differential expression of immune response genes in E56 Vs E42 tissue suggest different candidates for the observed reduced immunogenicity displayed by the tissue harvested at E42. Encouraging preliminary results suggest that marked growth and development of such implants, under tolerable immune suppression, can be attained in non-human primates and lead to independence of exogenous insulin.
Parallel studies investigating the various parameters critical for successful transplantation and growth of fetal porcine spleen showed that this new source could be used for the treatment of monogenic diseases. As a proof of concept we demonstrated efficacy in the correction of factor VIII KO hemophilic mice (7). An important basic question raised by these studies relates to organ size control. Thus our studies revealed new candidates involved in the control of organ size under conditions, which might lead to over sized organs . Taken together, by measuring growth potential of human or pig embryonic precursor tissues in different mouse models, we were able to interrogate basic questions related to differentiation and immunogenicity as well as to define optimal ‘window’ embryonic transplants which could afford a new source in organ transplantation. Future studies will attempt to define the minimal immune suppression which might enable engraftment and growth of different pig embryonic tissues in humans, and to further charceterize in our transplantation assay key molecules in organ size control . In addition, the role of different immune response genes in the reduced immunogenicity of early embryonic pancreatic tissue, will be further studied .