EXCEED THE SPACE PROVIDED. Intrauterine bone marrow transplantation (BMT) holds considerable promise as a therapeutic approach for many congenital immune, hematologic and enzyme deficiencies. Based upon the current premise that the early fetal environment is favorable to the development of immune tolerance, mismatched cells should engraft within the fetus without being rejected or causing graft-versus-host disease (GVHD). Our overall question asks whether the fetus can support substantial long term engraftment following in utero BMT. The exact conditions necessary to achieve stable chimerism have not been systematically studied in terms of donor cell dosage, recipient gestational age, and production and avoidance of GVHD. We hypothesize that these parameters are key to safe and successful allogeneic in utero BMT in an established canine model which has applicability to the human. Therefore, the specific aims of this proposal are:
Aim #1 : Determine the effects of gestational age and donor cell dosage on degree and sites of engraftment following in utero BMT. Gestational age will be systematically varied. Hematopoietic stem cell (HSC) dose response studies will be done, subsequently varying the number of donor T-cells. We will also evaluate the complications and mortality resulting from overengraftment and/or GVHDo Hypothesis 1A: Fetal canine recipients from 32 to 38 days of gestation will show progressively higher levels of engraftment at progressively earlier gestational ages and higher donor HSC doses of >108 HSC/kg fetal weight. Hypothesis 1B: Donor T-cell dosage must fall within a relatively narrow range in order to achieve sustained engraftment and avoid GVHD, and relatively small adjustments in donor T-cell dosage appreciably alter degree of engraftment.
Aim #2. Determine the functional immune capacity of fetal canines. Immunologic assays will be conducted on fetal pups from day 32 through day 48. Hypothesis: Fetal immunologic function increases progressively during mid-gestation in canines and tolerance to foreign antigens decreases after day 40. These studies are designed to increase our understanding of the early events and pathology associated with intrauterine HSC infusion. This information may lead to enhancement of chimerism with a reduction in morbidity and mortality. PERFORMANCE SITE ========================================Section End===========================================
| Petersen, Scott M; Gendelman, Mariya; Murphy, Kathleen M et al. (2013) In utero hematopoietic stem cell transplantation in canines: exploring the gestational age window of opportunity to maximize engraftment. Fetal Diagn Ther 33:116-21 |
