The Shizuru Lab

Lab Goals

The research interests are to understand the cellular and molecular basis of resistance to engraftment of transplanted allogeneic bone marrow (BM) cells and to understand the way in which BM grafts modify immune responses. This research complements our interest in clinical BM transplantation and aspects of these studies are aimed at solving some of the major problems of BM transplantation which include graft-vs-host disease and BM engraftment failure. Conventional BM transplantation involves the transfer of heterogeneous populations of cells composed of rare hematopoietic stem cells (HSCs) and differentiated blood cell types. To study these issues our approach has been to transplant phenotypically purified cells under defined conditions. The specific projects in my laboratory include:

1. Identification of the cells and molecules responsible for resistance to engraftment of purified allogeneic HSCs. We and others have shown that cells with NK determinants constitute a significant barrier to allogeneic HSC engraftment, and that transplanted whole BM contains a population that facilitates engraftment. In these experiments our approach to identify the cell population(s) and mechanism by which HSC engraftment is resisted is to use recipient mice from strains that lack defined immune functions. We are studying the cells in BM and spleen that are bound and/or depleted by a-ASGMI, and in this way identify the candidate barrier populations.
2. Use of transplants of purified HSCs to induce tolerance to allo- and autoantigens, and study of the mechanisms by which such tolerance is induced. We continue to develop preclinical models for organ tolerance induction and treatment of autoimmune disease by using cell specific therapy. One goal is to decrease the morbidity of the recipient preparative regimen and to determine the lowest level of chimerism needed to induce immune tolerance. We propose to test donor/host strain combinations most relevant to human disease, including minor mismatched and haploidentical grafts.
3. Identification of the cells and molecules that confer graft vs leukemia/lymphoma (GVL) effects. We have developed a model of B cell lymphoma relapse after HSC transplant. To date our studies show that while purified allogeneic HSCs have no GVL activity, a population of BM cells that express CD3 and CD8 have significant GVL activity, and do not cause GVHD at the cell doses administered.