Bone marrow expressing a diabetes resistance MHC class II allele: diabetes deviation by chronic immune stimulation.

The major histocompatibility complex (MHC) of the type 1 diabetes-prone NOD mouse lacks a functional class II H2-Ea gene such that antigen presenting cells (APCs) are I-E null. Transgenic expression of Ea in NOD mice both restores I-E expression and confers complete protection from diabetes progression. Non-myeloablative neonatal transplantation of bone marrow cells from such I-E+ transgenic donors into NOD recipients resulted in low-level but long-term haematopoietic stem cell (HSC) engraftment.

Attenuation of murine lysosomal storage disease by allogeneic neonatal bone marrow transplantation using costimulatory blockade and donor lymphocyte infusion without myeloablation.

Treatment of nonmalignant childhood disorders by bone marrow transplantation (BMT) is limited by toxicity from preparatory regimens and immune consequences associated with engraftment of allogeneic donor cells. Using costimulatory blockade (anti-CD40L mAb and CTLA-4Ig) combined with high-dose BMT in nonablated neonates, we obtained engraftment and established tolerance using both partially MHC mismatched (H2g7 into H2b) and fully mismatched BM (H2s into H2b). Recipients were mucopolysaccharidosis type VII (MPS VII) mice with lysosomal storage disease in order to assess therapeutic outcome.

Transplanted ER-MP12hi20-58med/hi myeloid progenitors produce resident macrophages from marrow that are therapeutic for lysosomal storage disease.

Lysosomal storage diseases (LSD) respond to bone marrow (BM) transplantation when donor-derived cells deliver needed enzyme. Hypothetically, the ubiquitous resident macrophages (MPhi) are the primary delivery vehicle of therapeutic protein. In mucopolysaccharidosis type VII (MPS VII) mice with LSD, transplanted mature MPhi reduce undegraded glycosaminoglycans (GAG) in the lysosome but are incapable of self-renewal, leading to return of storage after 1 month.

Donor cell expansion is delayed following nonablative in utero transplantation to treat murine mucopolysaccharidosis type VII.

To block development of progressive childhood diseases, in utero transplantation (IUTx) requires immediate and significant donor peripheral blood (PB) cell amplification. To date, negligible and nontherapeutic donor PB cell levels have been observed postnatally, except in patients with immunodeficiency diseases. Donor cell fate in utero still is not clear.

Successful allogeneic neonatal bone marrow transplantation devoid of myeloablation requires costimulatory blockade.

A significant number of nonmalignant, progressive childhood disorders respond to bone marrow transplantation (BMT). Toxic myeloablative pretreatment regimens, graft failure, and graft-vs-host disease complicate the utility of BMT for neonatal treatment. We recently demonstrated high-dose BMT in neonatal animals enables chimeric engraftment without toxic myeloablation.

Delayed administration of carrier marrow can decrease competition on donor stem cells during engraftment and maintain radioprotection of the host.

Objective: The goal of this study was to determine if competitive pressure was placed on hematopoietic stem cells (HSC) by a coinjected "carrier" population that maintains short-term survival of the host. Our hypothesis was that delayed introduction of "carrier" cells would increase engraftment of donor HSC.

Materials And Methods: Competitive repopulation assays were performed using genetically distinguishable whole bone marrow (BM) populations.