http://repub.eur.nl/res/aut/9176/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/10697/ 2007-11-28T00:00:00Z Allogeneic stem cell transplantation (allo-SCT) has been established as important treatment modality for patients with hematological malignancies, aplastic anemia, and inborn errors of hematopoietic progenitor cells. Nevertheless, major lethal and non-lethal complications still prohibit a full implementation of allo-SCT. Opportunistic infections are considered a frequent and serious complication of allo-SCT due to impaired immune reconstitution following allo-SCT. Delayed recovery of thymus- dependent naive CD4+ T cells, in particular, is associated with significant susceptibility to opportunistic infections and subsequent transplant-related morbidity and mortality. Improvement of thymopoiesis following allo-SCT has become subject of interest. Interleukin-7 (IL-7) has been identified as key regulator of T-cell lymphopoiesis and peripheral homeostatic T-cell expansion. Preclinical evaluation of posttransplant administration of IL-7 has shown effects both on thymic T-cell development and peripheral T- cell expansion. Considerable controversy exists with respect to IL-7 and its effect on alloreactivity. The work as described in this thesis aims to further clarify the immunorestorative capacities of posttransplant IL-7 administration and its role in alloreactivity using experimental murine transplantation models. http://repub.eur.nl/res/pub/8154/ 2003-01-01T00:00:00Z Interleukin-7 (IL-7) has been shown to enhance thymic output of newly developed T cells following bone marrow transplantation (BMT) in mice. In addition, IL-7 may affect peripheral expansion of T cells. In order to study the relative contribution of thymopoiesis versus peripheral T-cell expansion in the setting of compromised thymopoiesis, we have applied IL-7 in an experimental stem cell transplantation model using T cell-deficient RAG-1(-/-) mice. C57BL/6 RAG-1(-/-) mice received transplants of syngeneic T-cell-depleted (TCD) bone marrow (Ly5.1) with or without supplemented T cells (Ly5.2). IL-7 was administered until day 63 after BMT. Peripheral blood T- and B-cell recovery was quantified by flow cytometry and thymopoiesis was studied by quantification of T-cell receptor rearrangement excision circles (TRECs). In mice receiving a T-cell-replete BMT, IL-7 selectively expanded mature CD45.2+ T cells without affecting the recovery of new bone marrow-derived CD45.1+ T cells. In contrast, IL-7 significantly enhanced the recovery of bone marrow-derived T cells after TCD BMT. Quantification of TRECs in mice receiving a TCD BMT revealed that enhanced T-cell recovery following IL-7 treatment resulted from a strong expansion of newly developed naive T cells. These results suggest that peripheral expansion of recent thymic emigrants or mature T cells may be a preferential mechanism by which IL-7 enhances T-cell recovery after BMT http://repub.eur.nl/res/pub/9294/ 2000-01-01T00:00:00Z We evaluated the efficacy, toxicity, and outcome of preemptive ganciclovir (GCV) therapy in 80 cytomegalovirus (CMV)-seropositive patients allografted between 1991 and 1996 and compared their outcome to 35 seronegative patients allografted during the same period. Both cohorts were comparable with respect to diagnosis and distribution of high- versus standard-risk patients. All patients received a stem cell graft from an HLA-identical sibling donor, and grafts were partially depleted of T cells in 109 patients. Patients were monitored for CMV antigenemia by leukocyte expression of the CMV-pp65 antigen. Fifty-two periods of CMV reactivation occurring in 30 patients were treated preemptively with GCV. A favorable response was observed in 48 of 50 periods, and only 2 patients developed CMV disease: 1 with esophagitis and 1 with pneumonia. Ten of 30 treated patients developed GCV-related neutropenia (less than 0.5 x 10(9)/L), which was associated with a high bilirubin at the start of GCV therapy. Overall survival at 5 years was 64% in the CMV-seronegative cohort and 40% in the CMV-seropositive cohort (P =.01). Increased treatment-related mortality accounted for inferior survival. CMV seropositivity proved an independent risk factor for developing acute graft-versus-host disease, and acute graft-versus-host disease predicted for higher treatment-related mortality and worse overall survival in a time-dependent analysis. We conclude that, although CMV disease can effectively be prevented by preemptive GCV therapy, CMV seropositivity remains a strong adverse risk factor for survival following partial T-cell-depleted allogeneic stem cell transplantation.