Abstract

The goal of these studies is to optimize a well-studied protocol for the induction of specific allograft prolongation that requires neither extensive donor pretreatment nor chronic immunosuppression. In this procedure recipients are treated with a short-term course of antilymphocyte serum (ALS) followed by an injection of donor bone marrow cells. Mice treated in this fashion exhibit a state of specific allograft unresponsiveness mediated at least in part by donor-derived suppressor cells. Successful application of this system to renal allografts in dogs, and monkeys has been achieved, and recent application to man suggests an important clinical feasibility. Our laboratory has extensively characterized, and prepared fractions highly enriched for the bone marrow cell active in the prolongation of allografts. The injection of fractionated bone marrow has been shown to be superior to unfractionated bone marrow as measured by the extent of graft prolonging ability. Proposed experiments seek (1) to optimize the ALS/fractionated bone marrow protocol in canine renal allograft experiments by including cyclosporin A in the treatment protocol; (2) to expand the application of neonatal tissue allografts which have been shown to exhibit superior survival in the ALS and bone marrow system; (3) to define optimal homing patterns of injected bone marrow for the purpose of targeting active cells to relevant sites; (4) to study the nature of cellular interaction during the immediate posttreatment period in recipient animals; and (5) to produce a monoclonal antibody to cell-surface markers unique to the active bone marrow cell. In addition to continuing the clinically relevant studies in dogs, experiments will be performed in skin and islet allograft models in mice. Promising results from the small animal studies will be immediately tested in the canine renal allograft model. Long-term clinical and immunological follow up in dogs should provide insight into the application of these protocols to man.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK033466-11
Application #
3231847
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1983-08-01
Project End
1994-07-31
Budget Start
1991-08-01
Budget End
1992-07-31
Support Year
11
Fiscal Year
1991
Total Cost
Indirect Cost

  Institution

Name
Northeastern University
Department
Type
Schools of Allied Health Profes
DUNS #
039318308
City
Boston
State
MA
Country
United States
Zip Code
02115

  Publications

Masli, S; De Fazio, S R; Gozzo, J J (1997) Expression of dendritic cell markers on bone marrow cells in a fraction enriched for the ability to prolong skin allograft survival in ALS-treated murine recipients. Transplant Proc 29:1147-8
De Fazio, S R; Plowey, J M; Hartner, W C et al. (1996) Late adjunctive therapy with single doses of rapamycin in skin-allografted mice treated with antilymphocyte serum and donor bone marrow cells. Transpl Immunol 4:105-12
De Fazio, S R; Masli, S; Gozzo, J J (1996) Effect of monoclonal anti-CD4 and anti-CD8 on skin allograft survival in mice treated with donor bone marrow cells. Transplantation 61:104-10
Gozzo, J J; Plowey, J; Hartner, W C et al. (1995) Importance of schedule of administration of adjunctive, short-term immunosuppression in ALS- and bone marrow cell-treated, skin-allografted mice. Transplant Proc 27:169-70
Hartner, W C; Markees, T G; De Fazio, S R et al. (1995) Effect of early administration of donor bone marrow cells on renal allograft survival in dogs treated with antilymphocyte serum and cyclosporine. Transplantation 59:131-4
De Fazio, S R; Markees, T G; Hartner, W C et al. (1995) Specificity requirement of donor bone marrow cells that prolong allograft survival: implications for a veto cell mechanism of action. Transplant Proc 27:171-3
Hartner, W C; Van der Werf, W J; Lodge, J P et al. (1995) Effect of rapamycin on renal allograft survival in canine recipients treated with antilymphocyte serum, donor bone marrow, and cyclosporine. Transplantation 60:1347-50
Khouri, W; Masli, S; De Fazio, S R et al. (1994) Effect of asialofetuin on prolongation of skin allograft survival by donor bone marrow cells. Transplantation 57:440-6
De Fazio, S R; Plowey, J; Hartner, W C et al. (1994) Effect of single-dose, late treatment with rapamycin on skin allograft survival in ALS- and donor bone marrow cell-treated mice. Transplant Proc 26:3102-3
Pourshadi, M; De Fazio, S R; Gozzo, J J (1993) Abrogation of secondary skin allograft rejection by veto-like cells in donor bone marrow. Transplantation 56:385-90

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