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Jane E Barker

Publications and source records attributed to Jane E Barker.

5 recordsLinked to original sources
PubMed2003

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. Reagents that block T cell costimulation (anti-CD40L mAb and/or CTLA-4Ig) establish tolerant allogeneic engraftment in adult recipients. Donor lymphocyte infusion (DLI) re-establishes failing grafts and treats malignant relapse via a graft-vs-leukemia response. In this study, we tested the hypothesis that combining these approaches would allow tolerant allogeneic engraftment devoid of myeloablation in neonatal normal and mutant mice with lysosomal storage disease. Tolerant chimeric allogeneic engraftment was achieved before DLI only in the presence of both anti-CD40L mAb and CTLA-4Ig. DLI amplified allografts to full donor engraftment long-term. DLI-treated mice either maintained long-term tolerance or developed late-onset chronic graft-vs-host disease. This combinatorial approach provides a nontoxic method to establish tolerant allogeneic engraftment for treatment of progressive childhood diseases.

Abatacept↗
PubMed2003

Increased erythrocyte adhesion in mice and humans with hereditary spherocytosis and hereditary elliptocytosis.

Mice with disruptions of the red blood cell (RBC) cytoskeleton provide severe hemolytic anemia models in which to study multiorgan thrombosis and infarction. The incidence of cerebral infarction ranges from 70% to 100% in mice with alpha-spectrin deficiency. To determine whether mutant RBCs abnormally bind adhesive vascular components, we measured adhesion of mouse and human RBCs to immobilized human thrombospondin (TSP) and laminin (LM) under controlled flow conditions. Mutant RBCs had at least 10-fold higher adhesion to TSP compared with normal RBCs (P <.006). Mutant relative to unaffected RBC adhesion to LM was significantly (P <.01) increased as well. Treatment of RBCs with the anionic polysaccharide dextran sulfate inhibited mutant RBC adhesion to TSP (P <.001). Treatment of RBCs with antibodies to CD47 or the CD47-binding TSP peptide 4N1K did not inhibit TSP adhesion of RBCs. Previously, we have shown that infarcts in alpha-spectrin-deficient sph/sph mice become histologically evident beginning at 6 weeks of age. TSP adhesion of RBCs from 3- to 4- and 6- to 8-week-old sph/sph mice was significantly higher than RBCs from adult mice (> 12 weeks old; P <.005). While the mechanism of infarction in these mice is unknown, we speculate that changes in RBC adhesive characteristics contribute to this pathology.

Animals↗
PubMed2002

Mutations in the murine erythroid alpha-spectrin gene alter spectrin mRNA and protein levels and spectrin incorporation into the red blood cell membrane skeleton.

Tetramers of alpha- and beta-spectrin heterodimers, linked by intermediary proteins to transmembrane proteins, stabilize the red blood cell cytoskeleton. Deficiencies of either alpha- or beta-spectrin can result in severe hereditary spherocytosis (HS) or hereditary elliptocytosis (HE) in mice and humans. Four mouse mutations, sph, sph(Dem), sph(2BC), and sph(J), affect the erythroid alpha-spectrin gene, Spna1, on chromosome 1 and cause severe HS and HE. Here we describe the molecular alterations in alpha-spectrin and their consequences in sph(2BC)/sph(2BC) and sph(J)/sph(J) erythrocytes. A splicing mutation, sph(2BC) initiates the skipping of exon 41 and premature protein termination before the site required for dimerization of alpha-spectrin with beta-spectrin. A nonsense mutation in exon 52, sph(J) eliminates the COOH-terminal 13 amino acids. Both defects result in instability of the red cell membrane and loss of membrane surface area. In sph(2BC)/sph(2BC), barely perceptible levels of messenger RNA and consequent decreased synthesis of alpha-spectrin protein are primarily responsible for the resultant hemolysis. By contrast, sph(J)/sph(J) mice synthesize the truncated alpha-spectrin in which the 13-terminal amino acids are deleted at higher levels than normal, but they cannot retain this mutant protein in the cytoskeleton. The sph(J) deletion is near the 4.1/actin-binding region at the junctional complex providing new evidence that this 13-amino acid segment at the COOH-terminus of alpha-spectrin is crucial to the stability of the junctional complex.

Animals↗
PubMed2002

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. Donor BM was competed against carrier BM that was coinjected or injected 3 or 4 days later. Radioprotection with delayed carrier injection also was examined by performing the initial HSC transplantation with Hoechst(lo) side population (SP) cells. SP HSC incubated with cytokines and BM stroma to stimulate cell cycling before transplantation also were tested using coinjection or delayed carrier administration. RESULTS: Delayed introduction of carrier whole BM increased peripheral expansion of donor whole BM, freshly isolated HSC, or cytokine-stimulated HSC compared to coinjection with carrier cells. A 3-day delay in carrier administration maintained radioprotection in 100% of lethally irradiated recipients of highly enriched HSC, whereas a 4-day delay did not rescue these recipients from death. When recipients are rescued, recovering host marrow can compete against donor HSC unless sufficient donor cells are injected. CONCLUSIONS: Delayed introduction of carrier BM significantly increases donor HSC engraftment and peripheral expansion by reducing competition in the host. Competition by a coinjected carrier cell population or recovery of host marrow significantly reduces the therapeutic efficacy of normal or in vitro manipulated donor HSC.

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