After allogeneic stem cell transplantation (alloSCT), patient-derived stem cells that survived the pretransplantation conditioning compete with engrafting donor stem cells for bone marrow (BM)... Show moreAfter allogeneic stem cell transplantation (alloSCT), patient-derived stem cells that survived the pretransplantation conditioning compete with engrafting donor stem cells for bone marrow (BM) repopulation. In addition, donor-derived alloreactive T cells present in the stem cell product may favor establishment of complete donor-derived hematopoiesis by eliminating patient-derived lymphohematopoietic cells. T cell-depleted alloSCT with sequential transfer of potentially alloreactive T cells by donor lymphocyte infusion (DLI) provides a unique opportunity to selectively study how competitive repopulation and allo-immunologic pressure influence lymphohematopoietic recovery. This study aimed to determine the relative contribution of competitive repopulation and donor-derived anti-recipient alloimmunologic pressure on the establishment of lymphohematopoietic chimerism after alloSCT. In this retrospective cohort study of 281 acute leukemia patients treated according to a protocol combining alemtuzumab-based T cell-depleted alloSCT with prophy-lactic DLI, we investigated engraftment and quantitative donor chimerism in the BM and immune cell subsets. DLI-induced increase of chimerism and development of graft-versus-host disease (GVHD) were analyzed as complementary indicators for donor-derived anti-recipient alloimmunologic pressure. Profound suppression of patient immune cells by conditioning sufficed for sustained engraftment without necessity for myeloablative conditioning or development of clinically significant GVHD. Although 61% of the patients without any DLI or GVHD showed full donor chimerism (FDC) in the BM at 6 months after alloSCT, only 24% showed FDC in the CD4+ T cell compartment. In contrast, 75% of the patients who had received DLI and 83% of the patients with clinically significant GVHD had FDC in this compartment. In addition, 72% of the patients with mixed hematopoiesis receiving DLI converted to complete donor-derived hematopoiesis, of whom only 34% developed clinically significant GVHD. Our data show that competitive repopulation can be sufficient to reach complete donor-derived hematopoiesis, but that some alloimmunologic pressure is needed for the establishment of a completely donor-derived T cell compartment, either by the development of GVHD or by administration of DLI. We illustrate that it is possible to separate the graft-versus-leukemia effect from GVHD, as conversion to durable complete donor-derived hematopoiesis following DLI did not require induction of clinically significant GVHD. (c) 2023 The American Society for Transplantation and Cellular Therapy. Show less
Heiden, P.L.J. van der; Egmond, H.M. van; Veld, S.A.J.; Meent, M. van de; Eefting, M.; Wreede, L.C. de; ... ; Jedema, I. 2018
The clinical manifestations and outcomes of systemic lupus erythematosus (SLE) are remarkably heterogeneous. In this thesis, issues relating to the diagnosis and prognosis of SLE were studied,... Show moreThe clinical manifestations and outcomes of systemic lupus erythematosus (SLE) are remarkably heterogeneous. In this thesis, issues relating to the diagnosis and prognosis of SLE were studied, focussing on the application of histopathologic evaluation in conjunction with clinical features in the setting of lupus nephritis (LN) and neuropsychiatric SLE (NP-SLE). In the first part, we demonstrated that classification criteria for SLE cannot be unequivocally applied to patients from nephrology clinics who present with full house glomerular deposits suggestive of LN/SLE. The patients with full house glomerular deposits without clinical SLE represented a distinct entity with a remarkably poor renal outcome. In the second part, clinical and histopathologic determinants of renal outcome were investigated to improve prognostication in LN. First, we identified a subgroup of patients with class III/IV LN with favourable renal outcome indicating that the current classification warrants refinement. Next, we identified prognosticators that may add to the current histopathologic classification of LN. The last part of this thesis was focused on the aetiopathogenesis of SLE, in which the complement system was identified as an important player and thereby therapeutic target in neuropsychiatric lupus and in which pregnancy-acquired microchimerism in relation to the occurrence of SLE was further investigated. Show less
Chimerism after orthotopic liver transplantation (OLT) is the main focus of the studies described in this thesis. The first study showed that chimerism of different cell lineages within the liver... Show moreChimerism after orthotopic liver transplantation (OLT) is the main focus of the studies described in this thesis. The first study showed that chimerism of different cell lineages within the liver graft does occur after OLT. Subsequently, in allogeneic blood stem cell recipients, chimerism was demonstrated in liver tissue, providing evidence that circulating progenitor cells can indeed differentiate into parenchymal liver cells.The secondary focus of this thesis is on matrix metalloproteinases (MMPs). These proteolytic enzymes are involved in a wide variety of physiological and disease-related matrix remodeling processes. MMP-2 and MMP-9 gene promotor polymorphisms were assessed of OLT donors and recipients in relation to ischemia/reperfusion injury, acute rejection and non-anastomotic biliary strictures after transplantation. We performed a side study, in which we evaluated the value of serum liver chemistry profile and abdominal ultrasound for detecting clinically relevant biliary strictures using time-dependent multivariate regression analysis. The two main themes, chimerism and MMPs, merge in the final chapter of this thesis. In liver transplant recipients with donor/recipient mismatches for MMP gene polymorphisms chimerism was studied, in both liver biopsies as in peripheral blood after OLT. Show less
This thesis describes clinical, cytological, immunological and pharmacological aspects of acute childhood leukaemia and allogeneic stem cell transplantation(SCT), with the emphasis on the analysis... Show moreThis thesis describes clinical, cytological, immunological and pharmacological aspects of acute childhood leukaemia and allogeneic stem cell transplantation(SCT), with the emphasis on the analysis of potential improvements in risk stratification and possible treatment adaptation, in order to decrease relapse frequency and disease-related death. Firstly, to study the role of chemokine receptor/ligand interactions in the context of extramedullary leukaemia, we analyzed the homing receptor expression on leukemic blast cells in skin or intestine, peripheral blood and bone marrow of patients with T-ALL en AML, respectively. Secondly, the treatment results of 132 children, who received an allogeneic HLA-identical SCT for acute leukaemia was evaluated, showing the effect of biologically effective TBI dose on relapse risk. Thirdly, to optimize the use of Cyclosporin A(CsA) for adequate Graft-versus-host disease(GVHD) prophylaxis and to avoid drug toxicity, we investigated the pharmacokinetics of CsA in children after SCT, and showed that monitoring CsA exposure early after SCT may provide a tool to influence outcome. Finally, to gain a better understanding of the mechanism of chimerism induction of endothelial and epithelial cells following allogeneic SCT, the occurrence of chimerism in relation to the conditioning regimen, time interval after SCT and development of GVHD was studied. Show less
The term __chimerism__ originates from Greek mythology and refers to the creature Chimaera, whose body was in front a lion, the back a serpent and the midsection a goat. In medicine, the term... Show moreThe term __chimerism__ originates from Greek mythology and refers to the creature Chimaera, whose body was in front a lion, the back a serpent and the midsection a goat. In medicine, the term chimerism refers to an individual, organ or part consisting of tissues of diverse genetic constitution. Pregnancy, blood transfusion and organ transplantation are potential causes of chimerism. In this thesis the occurrence of chimerism is investigated in different organs of healthy women, of women with the autoimmune disease Systemic Lupus Erythematosus (SLE) and of women that received a renal allograft. To demonstrate chimerism, male cells were detected in female organs by using in situ hybridization of the Y chromosome. Chimerism was found in 18% of healthy organs, in about 50% of organs derived from women with SLE and in none of the skin tumors investigated from female renal allograft recipients. In various organ types and both in women with and without sons and women with and without a transfusion history, chimerism was present. In this thesis we describe these results and review data from the ancient and recent literature. With all these data in hand, we speculate about the sources of chimerism and its implications on immunity. Show less
