INDUCTION OF KIDNEY TRANSPLANTATION TOLERANCE ACROSS MAJOR HISTOCOMPATIBILITY COMPLEX BARRIERS BY BONE MARROW TRANSPLANTATION IN MINIATURE SWINE

1991 ◽  
Vol 51 (4) ◽  
pp. 862-866 ◽  
Author(s):  
PHILIP C. GUZZETTA ◽  
THORALF M. SUNDT ◽  
TAKAO SUZUKI ◽  
ARNOLD MIXON ◽  
BRUCE R. ROSENGARD ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Major Histocompatibility Complex ◽  
Kidney Transplantation ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Transplantation Tolerance ◽  
Major Histocompatibility ◽  
Miniature Swine ◽  
Histocompatibility Complex

scholarly journals Bone marrow transplantation in major histocompatibility complex class II deficiency: a single-center study of 19 patients

Blood ◽  
1995 ◽  
Vol 85 (2) ◽  
pp. 580-587
Author(s):  
C Klein ◽  
M Cavazzana-Calvo ◽  
F Le Deist ◽  
N Jabado ◽  
M Benkerrou ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Major Histocompatibility Complex ◽  
Bone Marrow Transplantation ◽  
Mhc Class Ii ◽  
Marrow Transplantation ◽  
Class Ii ◽  
Combined Immunodeficiency ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Mhc Class Ii Deficiency

Major histocompatibility complex (MHC) class II deficiency (bare lymphocyte syndrome) is a rare inborn error of the immune system characterized by impaired antigen presentation and combined immunodeficiency. It causes severe and unremitting infections leading to progressive liver and lung dysfunctions and death during childhood. As in other combined immunodeficiency disorders, bone marrow transplantation (BMT) is considered the treatment of choice for MHC class II deficiency. We analyzed the files of 19 patients who have undergone BMT in our center. Of the 7 patients who underwent HLA- identical BMT, 3 died in the immediate posttransplant period of severe viral infections, whereas the remaining 4 were cured, with recovery of normal immune functions. Of the 12 patients who underwent HLA-haplo- identical BMT, 3 were cured, 1 was improved by partial engraftment, 7 died of infectious complications due to graft failure or rejection, and 1 is still immunodeficient because of engraftment failure. A favorable outcome in the HLA-non-identical BMT group was associated with an age of less than 2 years at the time of transplantation. All the patients with stable long-term engraftment had persistently low CD4 counts after transplantation (105 to 650/microL at last follow up), but no clear susceptibility to opportunistic infections despite persisting MHC class II deficiency on thymic epithelium and other nonhematopoietic cells. We conclude that HLA-identical and -haploidentical BMT can cure MHC class II deficiency, although the success rate of haploidentical BMT is lower than that in other combined immunodeficiency syndromes. HLA- haploidentical BMT should preferably be performed in the first 2 years of life, before the acquisition of chronic virus carriage and sequelae of infections.

scholarly journals Reduction of lethal graft-versus-host disease: transplantation of cultured murine bone marrow across minor histocompatibility differences

Blood ◽  
1985 ◽  
Vol 66 (3) ◽  
pp. 542-547 ◽  
Author(s):  
P Mauch ◽  
JM Lipton ◽  
BL Hamilton ◽  
J Obbagy ◽  
D Nathan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Major Histocompatibility Complex ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Cultured Cells ◽  
Major Histocompatibility ◽  
Spleen Cells ◽  
Host Disease ◽  
Murine Bone Marrow ◽  
Histocompatibility Complex

Abstract The murine bone marrow culture technique was used to prepare donor marrow for bone marrow transplantation across minor histocompatibility complex differences. Previous studies have shown that theta-positive cells are rapidly lost from such cultures and that transplantation of cultured marrow across major histocompatibility complex differences results in a delay in the development of lethal graft-v-host disease (GVHD). In this study, a total of 1 to 2 X 10(7) nonadherent cells (740 to 1560 CFUs [colony-forming units]) from three-day-old cultures were used as a source of donor marrow. Three strain combinations were evaluated; LP/J into C57BL/6; BIO.BR into CBA/J; and C57BL/6 into LP/J. Donor mice were immunized with recipient spleen cells prior to culture in order to increase the graft-v-host response. For LP/J marrow into C57BL/6 mice, 5 X 10(7) donor spleen cells transplanted along with the marrow were needed to induce lethal GVHD. However, lethal GVHD was seen without the addition of spleen cells for BIO.BR into CBA/J and C57BL/6 into LP/J strain combinations. Most animals receiving fresh marrow were dead of GVHD five weeks after transplantation. With the use of cultured marrow the three-month survival was 80%, 51%, and 93%, respectively, for LP/J into C57BL/6, BIO.BR into CBA/J, and C57BL/6 into LP/J strain combinations. Long-term donor engraftment in all recipient animals receiving cultured marrow was confirmed by analyzing hemoglobin polymorphisms between the strain combinations. These results demonstrate that in contrast to transplantation across major histocompatibility complex differences, the use of cultured cells for bone marrow transplantation across minor histocompatibility complex differences allows for engraftment while reducing the risk of lethal GVHD.

scholarly journals Bone marrow transplantation in major histocompatibility complex class II deficiency: a single-center study of 19 patients

Blood ◽  
1995 ◽  
Vol 85 (2) ◽  
pp. 580-587 ◽  
Author(s):  
C Klein ◽  
M Cavazzana-Calvo ◽  
F Le Deist ◽  
N Jabado ◽  
M Benkerrou ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Major Histocompatibility Complex ◽  
Bone Marrow Transplantation ◽  
Mhc Class Ii ◽  
Marrow Transplantation ◽  
Class Ii ◽  
Combined Immunodeficiency ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Mhc Class Ii Deficiency

Abstract Major histocompatibility complex (MHC) class II deficiency (bare lymphocyte syndrome) is a rare inborn error of the immune system characterized by impaired antigen presentation and combined immunodeficiency. It causes severe and unremitting infections leading to progressive liver and lung dysfunctions and death during childhood. As in other combined immunodeficiency disorders, bone marrow transplantation (BMT) is considered the treatment of choice for MHC class II deficiency. We analyzed the files of 19 patients who have undergone BMT in our center. Of the 7 patients who underwent HLA- identical BMT, 3 died in the immediate posttransplant period of severe viral infections, whereas the remaining 4 were cured, with recovery of normal immune functions. Of the 12 patients who underwent HLA-haplo- identical BMT, 3 were cured, 1 was improved by partial engraftment, 7 died of infectious complications due to graft failure or rejection, and 1 is still immunodeficient because of engraftment failure. A favorable outcome in the HLA-non-identical BMT group was associated with an age of less than 2 years at the time of transplantation. All the patients with stable long-term engraftment had persistently low CD4 counts after transplantation (105 to 650/microL at last follow up), but no clear susceptibility to opportunistic infections despite persisting MHC class II deficiency on thymic epithelium and other nonhematopoietic cells. We conclude that HLA-identical and -haploidentical BMT can cure MHC class II deficiency, although the success rate of haploidentical BMT is lower than that in other combined immunodeficiency syndromes. HLA- haploidentical BMT should preferably be performed in the first 2 years of life, before the acquisition of chronic virus carriage and sequelae of infections.

scholarly journals Reduction of lethal graft-versus-host disease: transplantation of cultured murine bone marrow across minor histocompatibility differences

Blood ◽  
1985 ◽  
Vol 66 (3) ◽  
pp. 542-547
Author(s):  
P Mauch ◽  
JM Lipton ◽  
BL Hamilton ◽  
J Obbagy ◽  
D Nathan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Major Histocompatibility Complex ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Cultured Cells ◽  
Major Histocompatibility ◽  
Spleen Cells ◽  
Host Disease ◽  
Murine Bone Marrow ◽  
Histocompatibility Complex

The murine bone marrow culture technique was used to prepare donor marrow for bone marrow transplantation across minor histocompatibility complex differences. Previous studies have shown that theta-positive cells are rapidly lost from such cultures and that transplantation of cultured marrow across major histocompatibility complex differences results in a delay in the development of lethal graft-v-host disease (GVHD). In this study, a total of 1 to 2 X 10(7) nonadherent cells (740 to 1560 CFUs [colony-forming units]) from three-day-old cultures were used as a source of donor marrow. Three strain combinations were evaluated; LP/J into C57BL/6; BIO.BR into CBA/J; and C57BL/6 into LP/J. Donor mice were immunized with recipient spleen cells prior to culture in order to increase the graft-v-host response. For LP/J marrow into C57BL/6 mice, 5 X 10(7) donor spleen cells transplanted along with the marrow were needed to induce lethal GVHD. However, lethal GVHD was seen without the addition of spleen cells for BIO.BR into CBA/J and C57BL/6 into LP/J strain combinations. Most animals receiving fresh marrow were dead of GVHD five weeks after transplantation. With the use of cultured marrow the three-month survival was 80%, 51%, and 93%, respectively, for LP/J into C57BL/6, BIO.BR into CBA/J, and C57BL/6 into LP/J strain combinations. Long-term donor engraftment in all recipient animals receiving cultured marrow was confirmed by analyzing hemoglobin polymorphisms between the strain combinations. These results demonstrate that in contrast to transplantation across major histocompatibility complex differences, the use of cultured cells for bone marrow transplantation across minor histocompatibility complex differences allows for engraftment while reducing the risk of lethal GVHD.

A cure for murine sickle cell disease through stable mixed chimerism and tolerance induction after nonmyeloablative conditioning and major histocompatibility complex–mismatched bone marrow transplantation

Blood ◽  
2002 ◽  
Vol 99 (5) ◽  
pp. 1840-1849 ◽  
Author(s):  
Leslie S. Kean ◽  
Megan M. Durham ◽  
Andrew B. Adams ◽  
Lewis L. Hsu ◽  
Jennifer R. Perry ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Major Histocompatibility Complex ◽  
Bone Marrow Transplantation ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Marrow Transplantation ◽  
Tolerance Induction ◽  
Mixed Chimerism ◽  
Cell Disease ◽  
Histocompatibility Complex

The morbidity and mortality associated with sickle cell disease (SCD) is caused by hemolytic anemia, vaso-occlusion, and progressive multiorgan damage. Bone marrow transplantation (BMT) is currently the only curative therapy; however, toxic myeloablative preconditioning and barriers to allotransplantation limit this therapy to children with major SCD complications and HLA-matched donors. In trials of myeloablative BMT designed to yield total marrow replacement with donor stem cells, a subset of patients developed mixed chimerism. Importantly, these patients showed resolution of SCD complications. This implies that less toxic preparative regimens, purposefully yielding mixed chimerism after transplantation, may be sufficient to cure SCD without the risks of myeloablation. To rigorously test this hypothesis, we used a murine model for SCD to investigate whether nonmyeloablative preconditioning coupled with tolerance induction could intentionally create mixed chimerism and a clinical cure. We applied a well-tolerated, nonirradiation-based, allogeneic transplantation protocol using nonmyeloablative preconditioning (low-dose busulfan) and costimulation blockade (CTLA4-Ig and anti-CD40L) to produce mixed chimerism and transplantation tolerance to fully major histocompatibility complex–mismatched donor marrow. Chimeric mice were phenotypically cured of SCD and had normal RBC morphology and hematologic indices (hemoglobin, hematocrit, reticulocyte, and white blood cell counts) without evidence of graft versus host disease. Importantly, they also showed normalization of characteristic spleen and kidney pathology. These experiments demonstrate the ability to produce a phenotypic cure for murine SCD using a nonmyeloablative protocol with fully histocompatibility complex–mismatched donors. They suggest a future treatment strategy for human SCD patients that reduces the toxicity of conventional BMT and expands the use of allotransplantation to non–HLA-matched donors.

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