A novel application of cyclosporine A in nonmyeloablative pretransplant host conditioning for allogeneic BMT

Blood ◽  
2000 ◽  
Vol 96 (3) ◽  
pp. 1166-1172 ◽  
Author(s):  
Boris Nikolic ◽  
Guiling Zhao ◽  
Kirsten Swenson ◽  
Megan Sykes
Keyword(s):  
Bone Marrow ◽  
Cyclosporine A ◽  
Bone Marrow Cells ◽  
Corticosteroid Treatment ◽  
Marrow Transplant ◽  
Allogeneic Bone Marrow ◽  
Whole Body ◽  
Allogeneic Bone ◽  
Central Tolerance ◽  
Bone Marrow Engraftment

The treatment of mice with anti-CD4 and anti-CD8 monoclonal antibodies (mAbs) on day −5, plus 3 Gy whole body irradiation (WBI) and 7 Gy thymic irradiation (TI) on day 0, allows fully major-histocompatibility-complex–mismatched allogeneic bone marrow engraftment and the induction of immunologic tolerance. TI is required in this model to overcome alloreactivity and possibly to make “space” in the recipient thymus so that lasting central tolerance can be achieved. In addition to suppressing mature T cells in the periphery, Cyclosporine A (CYA) and glucocorticoids have a powerful influence on the thymus. In this study, we evaluated whether the administration of CYA to recipient mice for 12 days prior to bone marrow transplant (BMT), of glucocorticosteroids on the day of BMT, or a combination of both, could create space and overcome alloresistance in the thymus by specifically depleting immature and mature thymocytes prior to BMT. High levels of multilineage donor hematopoietic repopulation and specific transplantation tolerance were achieved in mice treated from days −15 to −3 with CYA (20 mg/kg/d subcutaneously), anti-CD4/CD8 mAbs on day −5, followed by 3 Gy WBI and 15 × 106 allogeneic bone marrow cells on day 0. Vβ analysis suggested a central deletional tolerance mechanism. The same treatment without CYA pretreatment allowed only transient chimerism, without tolerance. Corticosteroid treatment abolished the engraftment-promoting and tolerance-inducing effects of CYA. These results demonstrate a novel pretransplantation-only application of CYA, which facilitates allogeneic marrow engraftment with minimal conditioning, by creating thymic space and/or overcoming intrathymic alloresistance.

A novel application of cyclosporine A in nonmyeloablative pretransplant host conditioning for allogeneic BMT

Blood ◽  
2000 ◽  
Vol 96 (3) ◽  
pp. 1166-1172 ◽  
Author(s):  
Boris Nikolic ◽  
Guiling Zhao ◽  
Kirsten Swenson ◽  
Megan Sykes
Keyword(s):  
Bone Marrow ◽  
Cyclosporine A ◽  
Bone Marrow Cells ◽  
Corticosteroid Treatment ◽  
Marrow Transplant ◽  
Allogeneic Bone Marrow ◽  
Whole Body ◽  
Allogeneic Bone ◽  
Central Tolerance ◽  
Bone Marrow Engraftment

Abstract The treatment of mice with anti-CD4 and anti-CD8 monoclonal antibodies (mAbs) on day −5, plus 3 Gy whole body irradiation (WBI) and 7 Gy thymic irradiation (TI) on day 0, allows fully major-histocompatibility-complex–mismatched allogeneic bone marrow engraftment and the induction of immunologic tolerance. TI is required in this model to overcome alloreactivity and possibly to make “space” in the recipient thymus so that lasting central tolerance can be achieved. In addition to suppressing mature T cells in the periphery, Cyclosporine A (CYA) and glucocorticoids have a powerful influence on the thymus. In this study, we evaluated whether the administration of CYA to recipient mice for 12 days prior to bone marrow transplant (BMT), of glucocorticosteroids on the day of BMT, or a combination of both, could create space and overcome alloresistance in the thymus by specifically depleting immature and mature thymocytes prior to BMT. High levels of multilineage donor hematopoietic repopulation and specific transplantation tolerance were achieved in mice treated from days −15 to −3 with CYA (20 mg/kg/d subcutaneously), anti-CD4/CD8 mAbs on day −5, followed by 3 Gy WBI and 15 × 106 allogeneic bone marrow cells on day 0. Vβ analysis suggested a central deletional tolerance mechanism. The same treatment without CYA pretreatment allowed only transient chimerism, without tolerance. Corticosteroid treatment abolished the engraftment-promoting and tolerance-inducing effects of CYA. These results demonstrate a novel pretransplantation-only application of CYA, which facilitates allogeneic marrow engraftment with minimal conditioning, by creating thymic space and/or overcoming intrathymic alloresistance.

Transmission of thyrotoxicosis of autoimmune type by sibling allogeneic bone marrow transplant

1995 ◽  
Vol 133 (5) ◽  
pp. 564-566 ◽  
Author(s):  
John A Thomson ◽  
Rhoda M Wilson ◽  
Ian M Franklin
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplant ◽  
Marrow Transplant ◽  
Allogeneic Bone Marrow ◽  
Whole Body ◽  
Royal Infirmary ◽  
Allogeneic Bone ◽  
Autoimmune Thyroid ◽  
Allogeneic Bone Marrow Transplant ◽  
Circulating Lymphocytes

Thomson JA, Wilson RM, Franklin IM. Transmission of thyrotoxicosis of autoimmune type by sibling allogeneic bone marrow transplant. Eur J Endocrinol 1995;133:564–6. ISSN 0804–4643 This case report is on a 25-years-old male with acute myeloblastic leukaemia who achieved a remission after cytoxic therapy and whole-body irradiation. He received a bone marrow transplant from his human leucocyte antigen (HLA)-identical sister who had unsuspected autoimmune thyroid disease. Nine months later the bone marrow recipient developed thyrotoxicosis of autoimmune type at a time when his circulating lymphocytes were of 46XX karyotype. It is suspected that the thyrotoxicosis resulted from the transplantation of a clone of lymphocytes predisposed to the production of thyroid-stimulating autoantibodies. JA Thomson, University Department of Medicine, Glasgow Royal Infirmary, Queen Elizabeth Building, 10 Alexandra Parade, Glasgow G31 2ER, UK

scholarly journals CELLS INVOLVED IN THE IMMUNE RESPONSE

1969 ◽  
Vol 129 (4) ◽  
pp. 757-774 ◽  
Author(s):  
Nabih I. Abdou ◽  
Maxwell Richter
Keyword(s):  
Bone Marrow ◽  
Immune Response ◽  
Red Blood Cells ◽  
Blood Cells ◽  
Bone Marrow Cells ◽  
Allogeneic Bone Marrow ◽  
Red Cells ◽  
Allogeneic Bone ◽  
Sheep Red Blood Cells ◽  
Sheep Red Cells

Irradiated rabbits given allogeneic bone marrow cells from normal adult donors responded to an injection of sheep red blood cells by forming circulating antibodies. Their spleen cells were also capable of forming many plaques using the hemolysis in gel technique, and were also capable of undergoing blastogenesis and mitosis and of incorporating tritiated thymidine upon exposure to the specific antigen in vitro. However, irradiated rabbits injected with allogeneic bone marrow obtained from rabbits injected with sheep red blood cells 24 hr prior to sacrifice (primed donors) were incapable of mounting an immune response after stimulation with sheep red cells. This loss of reactivity by the bone marrow from primed donors is specific for the antigen injected, since the immune response of the irradiated recipients to a non-cross-reacting antigen, the horse red blood cell, is unimpaired. Treatment of the bone marrow donors with high-titered specific antiserum to sheep red cells for 24 hr prior to sacrifice did not result in any diminished ability of their bone marrow cells to transfer antibody-forming capacity to sheep red blood cells. The significance of these results, with respect to the origin of the antigen-reactive and antibody-forming cells in the rabbit, is discussed.

scholarly journals Relapse of chronic myeloid leukemia after allogeneic bone marrow transplant: the case for giving donor leukocyte transfusions before the onset of hematologic relapse

Blood ◽  
1994 ◽  
Vol 83 (11) ◽  
pp. 3377-3383 ◽  
Author(s):  
F van Rhee ◽  
F Lin ◽  
JO Cullis ◽  
A Spencer ◽  
NC Cross ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Myeloid Leukemia ◽  
Bone Marrow Transplant ◽  
Myeloid Leukemia ◽  
Marrow Transplant ◽  
Allogeneic Bone Marrow ◽  
Allogeneic Bone ◽  
Allogeneic Bone Marrow Transplant ◽  
Unrelated Donors ◽  
Polymerase Chain

Fourteen patients with chronic myeloid leukemia (CML) relapsing after allogeneic bone marrow transplant (BMT) were treated with leukocyte transfusions from the original marrow donor (sibling, n = 9; volunteer unrelated, n = 5). The relapse was defined at the molecular level in two cases, cytogenetically in five cases and hematologically in seven cases. Ten patients responded, seven of seven patients with cytogenetic/molecular relapse compared with three of seven with hematologic relapse (P < .03). All five recipients of cells from unrelated donors responded. Eight of the 10 responders have achieved polymerase chain reaction-negative status and this persisted in three patients for more than 2 years; no responder has shown sign of relapse. Reversible marrow aplasia occurred in two patients, both treated in hematologic relapse. Severe graft-versus-host disease occurred in four patients and was fatal in one. We confirm previous reports that donor leukocyte transfusions are effective in the management of CML in relapse after BMT. In this series, therapeutic intervention before the onset of hematologic relapse was associated with an increased likelihood of response and no marrow aplasia.

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