Prolonged immunodeficiency after allogeneic bone marrow transplantation (BMT) results in significant morbidity and mortality from infections, especially in adult recipients of an HLA-matched unrelated graft. Strategies to overcome post-transplant immunodefi-ciency could not only decrease the incidence of post-transplant infections, but could also enhance post-transplant cancer immunotherapy, including graft-versus- tumor activity, tumor vaccines or cellular therapies. We propose to study in well-defined and clinically relevant murine BMT models the effects of cytokine therapy with interleukin-7, Insulin Growth Factor-I, Keratinocyte Growth Factor, and/or Thymic Stromal Lymphopoietin on immune reconstitution. We will compare immune reconstitution in young and middle-aged patients, recipients of MHC-matched or MHC-mismatched allogeneic BMT, and recipients of allogeneic BMT with or without graft-versus-host-disease (GVHD).
In Specific Aim 1 we propose to analyze the effects of the administration of immunostimulatory cytokines on thymic and peripheral immune reconstitution after allogeneic BMT. We will perform a sequential analysis by flow cytometry and histology of the development of: (a) donor-derived cells in bone marrow, blood and lymphoid organs, (b) thymic positive and negative selection, (c) thymic architecture, (d) T-cell repertoire, and (e) peripheral T-cell homeostasis. Our analysis will focus specifically on T and B cell and dendritic cell development.
In Specific Aim 2 we propose to study the effects of immunostimulatory cytokine administration on the development of GVHD morbidity, mortality and specific GVHD-associated organ pathology after allogeneic BMT. The spefici effects on the pathophysiology of GVHD will be assessed: (a) donor T-cell expansion and activiation, (b) CD4/8 ratio, (c) serum cytokine levels and intracellular cytokine expression, and (d) macrphage activation.
In Specific Aim 3 we propose to study the effects of immunostimulatory cytokine administration on B and T-cell function in in vitro and in vivo assays. This will include an analysis of the effects on antimicrobial activity against Listeria in vivo and on graft-versus-tumor (GVT) activity of donor T-cells in several murine GVT models, including a model for donor leukocyte infusion (DLI). These studies can contribute to a better understanding of the severe post-transplant immunodeficiency and to the development of immunostimulatory cytokines as novel strategies to enhance post-transplant immune reconstitution without aggravating GVHD.
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