Yair Reisner Professor Yair Reisner
The Henry H. Drake Professor of Immunology
E-mail: yair.reisner@weizmann.ac.il
Phone: +972-8-934-4023
Fax: +972-8-947-4141
Location: Wolfson Bldg., Room 420

 Short Bio of Prof. Yair Reisner:

Professor Yair Reisner earned a BSc degree from the Hebrew University of Jerusalem in 1972, an MSc from the University of California at Berkeley in 1974, and a PhD from the Weizmann Institute of Science in 1978. He then spent several years as a research associate at the Memorial Sloan-Kettering Cancer Center in New York. He joined the Weizmann Institute in 1981. He served as the head of the Immunology Department between 2005-2014. Prof. Reisner research has been involved, for the past three decades with the subject of transplantation immunology and, more specifically, with questions relating to haploidnetical bone marrow transplantation (BMT) . Prof. Reisner achievements have been recognized by many awards including the Mortimer M. Borton Award for outstanding Research in Blood and Marrow Transplantation in 1996, the Maharshi Sushruta Award in 2002 , Abisch-Frenkel Prize for Excellence in the Life Sciences in 2004, Samuel and Paula Elekeles Prize for outstanding research in the Biomedical Field in 2012 and the Rappaport prize for excellence in biomedical research in 2014. Prof Reisner was selected in 2003 by the World Technology Network as one of “top five people in the field of Health and Medicine whose work is of the greatest likely long-term significance”. In 2003 he was awarded an Honorary Degree in Medicine from the University of Perugia, Italy. As of 2005 he serves as an elected member of the review panel for stem cell research in the State of California, USA. Between 2005-2007 Prof Reisner served as the president of Israel Stem Cell Society. He served as the associate editor of Experimental Hematology between 2004-2009 and he is currently associate editor of Frontiers in Alloimmunity and Transplantation and Deputy Editor of Bone Marrow Transplantation Journal.

 Research Interests:

Transplantation Immunology

Our research has been involved, for the past three decades with the subject of transplantation immunology and more specifically, with questions relating to haploidnetical (half-matching) bone marrow transplantation (BMT). Our early studies have paved the way for the wide use of bone marrow transplantation in patients without a matched donor. Initially, during the 80s our pioneering use of T cell depletion so as to prevent graft-versus-host disease has saved many lives of SCID patients (Lancet 1981, Blood 1983). In the 90s the discovery of the mechanism of action by which hematopoietic stem cells can overcome immune rejection (Nature Medicine 1995) has led to the use of ‘megadose’ hematopoietic stem cell transplants in more than 2000 leukemia patients for whom a donor was not available (N.Eng.J.Med. 1998; For Reviews see Blood 2013 and J. British Hematology 2015). Furthermore, our discovery that CD34 stem cells are endowed with veto activity, explaining their ability to overcome rejection in heavily conditioned leukemia patients , has led us to interrogate other veto cells in the immune system and their mechanism/s of action (Immunity 2000, Blood 2013, Reviewed in Regen. Med. 2015. ). Based on our insights from these studies we have shown in mouse models that central memory veto T cells if combined with megadose hematopoietic stem cells, can be used to enable tolerance induction to other donor cells, tissues or organs (Blood 2013) under minimal conditioning and without any need for post transplant immune suppression. This approach is currently in clinical trials and if successful it could pave the way for a new platform prior to organ transplantation or cell therapy.

Very recently, our long interest in immune tolerance has led to the discovery that perforin positive dendritic cells represent a unique immune regulatory subpopulation . Thus we demonstrated, using knockout mice, that this rare subpopulation controls inflammatory T cells in steady state and play a major regulatory role in metabolic syndrome and in experimental autoimmune encephlalomyelitis (Immunity 2015). Notably, mice lacking perforin-positive dendritic cells had high levels of cholesterol, early signs of insulin resistance, and molecular markers in their bloodstreams associated with heart disease and high blood pressure. A look at the immune systems of the mice revealed that they also had a different balance of immune T cells than normal. Moreover, when we removed these T cells from the mice, the lack of the dendritic cells no longer caused the animals to become obese or develop metabolic syndrome. Taken together, these results suggest that the normal role of the perforin-positive dendritic cells is to keep certain populations of inflammatory T cells under control. In the absence of these regulatory dendritic cells , when the brakes are taken off the inflammatory T cells, they cause inflammation in fat cells, which, in turn, leads to altered metabolism. Our lab is currently interrogating the role of perfroin positive dendritic cells in humans and continue to investigate in our mouse models the mechanism/s of action mediating the activity of these novel regulatory cells in steady state. .

In parallel, our team was able to apply insights developed in bone marrow transplantation to embryonic lung stem cell transplantation, demonstrating its curative potential for lung injury repair (Nature Medicine 2015). In particular, we confirmed in these work our major hypothesis that lung stem cells, like hematopoietic stem cells, occupy discrete niches and that transplantation of lung stem cells can succeed only if these niches are vacated prior to transplantation. Our ability to demonstrate marked donor chimerism in the lungs of recipient mice enables us to further investigate potential new candidates for lung stem cell therapy from different human sources including stem cells derived from allogeneic adult lungs or from autologous induced pluripotential stem cells (IPS). Likewise we are currently investigating potential new strategies for lung stem cell repair in mouse models of cystic fibrosis .

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 .

     Relevant Publications