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Improving T cell-mediated immunity and immunological tolerance after allo-SCT

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Title Improving T cell-mediated immunity and immunological tolerance after allo-SCT
Period 01 / 2007 - unknown
Status Current
URL http://www1.erasmusmc.nl/hematologie/index.php?cId=80
Research number OND1324878
Data Supplier Website EMC

Abstract

We have developed experimental murine SCT models to study the effect of cytokine intervention (such as IL-7, stem cell factor (SCF) , Flt3-Ligand and KGF) on T cell recovery and T cell function after SCT. Using these models, we demonstrated that that IL-7 improves the recovery of CD4+ and CD8+ T-cells following allo-SCT in T-cell-deficient mice by strong expansion of recent thymic emigrants or mature T cells present in the graft. IL-7 also enhanced the recovery of CD4+Foxp3+ Treg. In an allo-SCT rejection model, the IL-7 mediated enhanced recovery of Treg was associated with a concomitant reduction in bone marrow graft rejection. Also SCF and Flt3-Ligand accelerated and enhanced the recovery of peripheral T-cells especially after transplantation with a low dose of bone marrow cells. Lymphoid progenitor cell numbers were significantly increased in bone marrow (BM) of Flt3-L-treated mice prior to enhanced thymopoiesis. Improved T-cell recovery resulted in better immune competence against a post-BMT murine Cytomegalovirus infection. Our data indicate that Flt3-L may improve peripheral T-cell recovery by expansion of lymphoid progenitors and subsequent improved thymic seeding. Effects of SCF were largely confined to an improvement of thymopoiesis. Recently, we found that KGF enhances the peripheral CD4+Foxp3+ Treg pool (Fig. 1) by an early, transient and Treg-selective thymus-independent mechanism and thereafter by a non-selective thymus-dependent mechanism. Currently, it is studied whether the KGF-mediated expansion of the pool of peripheral Treg contributes to the inhibitory effects of KGF on graft rejection and GVHD. Following the favourable effects observed in our murine models, we will now proceed with a translational study in non-human primates, addressing the question whether KGF either alone or in combination with SCF, or in combination with IL-7, may result in improved recovery of newly developed T-cells and rapid recapitulation of thymopoiesis. If these studies will reproduce initial favourable findings in mice, we may be able to proceed to a clinical study within 2 years.

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Project leader Dr. E. Braakman

Related research (upper level)

Classification

D21500 Histology, cell biology
D21800 Immunology, serology
D23220 Internal medicine

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