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 immunodeficiency could not only decrease the incidence of post-transplant infections, but could also enhance post-transplant cancer immunotherapy, including graft-versus-tumor (GVT) 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 recipients, 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 specific effects on the pathophysiology of GVHD will be assessed: (a) donor T cell expansion and activation, (b) CD4/8 ratio, (c) serum cytokine levels and intracellular cytokine expression, and (d) macrophage 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 anti-microbial 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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