High-level allogeneic chimerism achieved by prenatal tolerance induction and postnatal nonmyeloablative bone marrow transplantation

Blood ◽  
2002 ◽  
Vol 100 (6) ◽  
pp. 2225-2234 ◽  
Author(s):  
William H. Peranteau ◽  
Satoshi Hayashi ◽  
Michael Hsieh ◽  
Aimen F. Shaaban ◽  
Alan W. Flake
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Cellular Therapy ◽  
Allogeneic Bone Marrow Transplantation ◽  
Tolerance Induction ◽  
Mixed Chimerism ◽  
Allogeneic Bone ◽  
Hematopoietic Stem ◽  
High Level

Abstract Clinical application of allogeneic bone marrow transplantation (BMT) has been limited by toxicity related to cytoreductive conditioning and immune response. In utero hematopoietic stem cell transplantation (IUHSCT) is a nonablative approach that achieves mixed chimerism and donor-specific tolerance but has been limited by minimal engraftment. We hypothesized that mixed chimerism achieved by IUHSCT could be enhanced after birth by nonmyeloablative total body irradiation (TBI) followed by same-donor BMT. To test this hypothesis, mixed chimerism was created by IUHSCT in a major histocompatibility complex-mismatched strain combination. After birth, chimeric animals received nonmyeloablative TBI followed by transplantation of donor congenic bone marrow cells. Our results show that: (1) low-level chimerism after IUHSCT can be enhanced to high-level chimerism by this strategy; (2) enhancement of chimerism is dependent on dose of TBI; (3) the mechanism of TBI enhancement is via a transient competitive advantage for nonirradiated hematopoietic stem cells; (4) engraftment observed in the tolerant, fully allogeneic IUHSC transplant recipient is equivalent to a congenic recipient; and (5) host-reactive donor lymphocytes are deleted with no evidence of graft-versus-host disease. This study supports the concept of prenatal tolerance induction to facilitate nonmyeloablative postnatal strategies for cellular therapy. If clinically applicable, such an approach could dramatically expand the application of IUHSCT.

Mixed Chimerism of Erythro- and Megakaryopoiesis following Allogeneic Bone Marrow Transplantation

2003 ◽  
Vol 109 (4) ◽  
pp. 176-183 ◽  
Author(s):  
J. Thiele ◽  
C. Wickenhauser ◽  
H.M. Kvasnicka ◽  
E. Varus ◽  
C. Schneider ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone Marrow ◽  
Mixed Chimerism ◽  
Allogeneic Bone

The Effects of Rapamune on NK Cell Post Bone Marrow Transplantation in Mice.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4858-4858
Author(s):  
Guanghua Chen ◽  
De Pei Wu ◽  
Ming Zhen Yang ◽  
Xiao Wen Tang ◽  
Ai-ning Sun
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Nk Cells ◽  
Marrow Transplantation ◽  
Nk Cell ◽  
Immunosuppressive Agents ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Hematopoietic Stem ◽  
Effector Cells

Abstract Natural killer(NK) cells are innate effector cells of the immune system, believed to limit viremia and tumor burden before the onset of adaptive T and B cell immunity. NK cells are potent effector cells in allogeneic bone marrow transplantation. NK cell activity is partially controlled through interactions between killer Ig-like receptors on NK cells and their respective HLA class I ligands. Immunosuppressive agents including cyclosporin, FK506 and Rapamune are utilized in clinical hematopoietic stem cell transplantation. Little is known about the effects of immunosuppressive agents on NK cells post bone marrow transplantation. The in vivo effects of Rapamune on NK cells were determined in an allogeneic bone marrow transplantation model. Splenic NK cell levels in recipients treated with Rapamune decrease markedly. NK cell proliferation and function are significantly decreased in the presence of Rapamune. Studying the differential effects of immunosuppressive drugs on NK cell function is critical in clinical hematopoietic stem cell transplantation.

Norethisterone Treatment, a Major Risk-Factor for Veno-Occlusive Disease in the Liver After Allogeneic Bone Marrow Transplantation

Blood ◽  
1998 ◽  
Vol 92 (12) ◽  
pp. 4568-4572
Author(s):  
Hans Hägglund ◽  
Mats Remberger ◽  
Sven Klaesson ◽  
Berit Lönnqvist ◽  
Per Ljungman ◽  
...  
Keyword(s):  
Risk Factors ◽  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Allogeneic Bone Marrow Transplantation ◽  
Occlusive Disease ◽  
Allogeneic Bone ◽  
Hla Antigen ◽  
Hematopoietic Stem ◽  
Heparin Prophylaxis

In this single-center study, we retrospectively analyzed incidence and risk factors for hepatic veno-occlusive disease (VOD) in 249 consecutive patients who underwent allogeneic hematopoietic stem cell transplantation between January 1990 and June 1995. Twenty-four of the 249 transplanted patients developed VOD. The probabilities of developing VOD were 17% among women and 7% in men (P = .01). In women treated with norethisterone, the incidence was 27% compared with 3% in women without this treatment (P = .007). One-year survival rates were 17% and 73% in patients with (n = 24) or without VOD (n = 225), respectively. The use of heparin prophylaxis (100 IE/kg/24 hours for 1 month) did not alter the incidence or 1-year mortality of VOD. In multivariate analysis, the following risk factors were significant: norethisterone treatment (P < .001), bilirubin >26 μmol/L before bone marrow transplantation (BMT) (P = .002), one HLA-antigen mismatch (P = .003), previous abdominal irradiation (P = .02), and conditioning with busulphan (P = .02). Our conclusion is that norethisterone treatment should not be used in patients undergoing BMT and heparin prophylaxis did not affect the incidence or mortality of VOD.

Congenital Erythropoietic Porphyria Successfully Treated by Allogeneic Bone Marrow Transplantation

Blood ◽  
1998 ◽  
Vol 92 (11) ◽  
pp. 4053-4058 ◽  
Author(s):  
I. Tezcan ◽  
W. Xu ◽  
A. Gurgey ◽  
M. Tuncer ◽  
M. Cetin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Allogeneic Bone Marrow Transplantation ◽  
Clinical Severity ◽  
Allogeneic Bone ◽  
Cutaneous Lesions ◽  
Hematopoietic Stem ◽  
Congenital Erythropoietic Porphyria

Abstract The long-term biochemical and clinical effectiveness of allogenic bone marrow transplantation (BMT) was shown in a severely affected, transfusion-dependent 18-month-old female with congenital erythropoietic porphyria (CEP), an autosomal recessive inborn error of heme biosynthesis resulting from mutations in the uroporphyrinogen III synthase (URO-synthase) gene. Three years post-BMT, the recipient had normal hemoglobin, markedly reduced urinary porphyrin excretion, and no cutaneous lesions with unlimited exposure to sunlight. The patient was homoallelic for a novel URO-synthase missense mutation, G188R, that expressed less than 5% of mean normal activity in Escherichia coli, consistent with her transfusion dependency. Because the clinical severity of CEP is highly variable, ranging from nonimmune hydrops fetalis to milder, later onset forms with only cutaneous lesions, the importance of genotyping newly diagnosed infants to select severely affected patients for BMT is emphasized. In addition, the long-term effectiveness of BMT in this patient provides the rationale for future hematopoietic stem cell gene therapy in severely affected patients with CEP.

Norethisterone Treatment, a Major Risk-Factor for Veno-Occlusive Disease in the Liver After Allogeneic Bone Marrow Transplantation

Blood ◽  
1998 ◽  
Vol 92 (12) ◽  
pp. 4568-4572 ◽  
Author(s):  
Hans Hägglund ◽  
Mats Remberger ◽  
Sven Klaesson ◽  
Berit Lönnqvist ◽  
Per Ljungman ◽  
...  
Keyword(s):  
Risk Factors ◽  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Allogeneic Bone Marrow Transplantation ◽  
Occlusive Disease ◽  
Allogeneic Bone ◽  
Hla Antigen ◽  
Hematopoietic Stem ◽  
Heparin Prophylaxis

Abstract In this single-center study, we retrospectively analyzed incidence and risk factors for hepatic veno-occlusive disease (VOD) in 249 consecutive patients who underwent allogeneic hematopoietic stem cell transplantation between January 1990 and June 1995. Twenty-four of the 249 transplanted patients developed VOD. The probabilities of developing VOD were 17% among women and 7% in men (P = .01). In women treated with norethisterone, the incidence was 27% compared with 3% in women without this treatment (P = .007). One-year survival rates were 17% and 73% in patients with (n = 24) or without VOD (n = 225), respectively. The use of heparin prophylaxis (100 IE/kg/24 hours for 1 month) did not alter the incidence or 1-year mortality of VOD. In multivariate analysis, the following risk factors were significant: norethisterone treatment (P &lt; .001), bilirubin &gt;26 μmol/L before bone marrow transplantation (BMT) (P = .002), one HLA-antigen mismatch (P = .003), previous abdominal irradiation (P = .02), and conditioning with busulphan (P = .02). Our conclusion is that norethisterone treatment should not be used in patients undergoing BMT and heparin prophylaxis did not affect the incidence or mortality of VOD.

scholarly journals High Dose Cyclophosphamide Treatment for Autoimmune Disorders

2002 ◽  
Vol 2 ◽  
pp. 1808-1815 ◽  
Author(s):  
Robert A. Brodsky
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Aldehyde Dehydrogenase ◽  
Marrow Transplantation ◽  
Allogeneic Bone Marrow Transplantation ◽  
Conditioning Regimen ◽  
Autoimmune Disorders ◽  
High Dose ◽  
Allogeneic Bone ◽  
Hematopoietic Stem

High-dose cyclophosphamide (200 mg/kg) was initially developed as a conditioning regimen for allogeneic bone marrow transplantation. Recently, high-dose cyclophosphamide without bone marrow transplantation has been employed as a method to induce durable treatment-free remissions in severe aplastic anemia and a variety of other severe autoimmune disorders. The premise underlying this approach is that high-dose cyclophosphamide is maximally immunosuppressive, but not myeloablative. Early hematopoietic stem cells are spared the cytotoxicity of cyclophosphamide because of their high levels of aldehyde dehydrogenase, an enzyme that confers resistance to the drug. Conversely, autoimmune effector cells (T cells, B cells, and NK cells) are exquisitely sensitive to high-dose cyclophosphamide because of their relatively low levels of aldehyde dehydrogenase. Intensive investigation is underway to determine which autoimmune disorders will most benefit and where in the natural history of these diseases to employ this rapidly developing therapy.

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