Control of the allogeneic reaction by naturally occuring regulatory T cells

Le polymorphisme et le polygénisme des complexes majeurs d’histocompatibilité (CMH) limitent les succès de la transplantation. En effet, les disparités, tant d’antigènes mineurs que majeurs, exposent le patient transplanté au risque de rejet et imposent l’administration d’un traitement immunosuppresseur. Ce dernier affecte de façon non spécifique l’ensemble des réponses immunitaires et augmente le risque d’infections mortelles et de cancers. En outre, ce traitement ne semble pas prévenir le rejet chronique. Des découvertes récentes ont confirmé l’existence de lymphocytes appelés régulateurs (Tregs) dont le rôle est de garantir l’homéostasie des réponses immunes afin qu’elles ne deviennent incontrôlées et pathologiques. Les Tregs classiquement décrits expriment de manière constitutive l’antigène CD4+, la chaîne alpha du récepteur de l’interleukine (IL)-2 (CD25) et le facteur de transcription Foxp3. Ils représentent 5 à 10% des lymphocytes CD4+ totaux. Les Tregs sont capables de réguler des lymphocytes alloréactifs et ont été décrits comme responsables du maintien de la tolérance d’allogreffe chez la souris. Mais jusqu'alors, les modèles employés pour démontrer l'importance des Tregs en transplantation utilisaient soit un traitement immunosuppresseur transitoire, soit des transferts de cellules T dans des souris lymphopéniques. Toutefois, ces derniers ne permettent pas de distinguer l'effet des Tregs sur la prolifération homéostatique des lymphocytes effecteurs de leur effet sur la réponse allogénique.Dans notre travail, nous montrons que les Tregs jouent un rôle prépondérant dans l’acceptation spontanée d’allogreffes en l’absence d’immunosuppresseur et en dehors d’un contexte lymphopénique chez la souris. En effet, la déplétion des Tregs du receveur par l’administration d’anticorps anti CD25 amplifie les réponses allogéniques de type Th1 et Th2 et, par conséquent, déclenche le rejet d’allogreffe. Les propriétés régulatrices des Tregs ne sont cependant pas illimitées. En effet, dans un second travail, nous décrivons, d’une part, leur incapacité à contrôler la production d’IL-17 par des lymphocytes CD4+CD25pos mémoires et, d’autre, part leur implication directe dans la différenciation de cellules Th17 au départ de lymphocytes CD4+CD25neg alloréactifs.Nous concluons donc que si les Tregs naturellement présents chez le receveur jouent un rôle primordial dans la protection du greffon contre des réponses de type Th1 ou Th2, ils pourraient néanmoins favoriser une voie alterne du rejet d’allogreffe dépendante de l’IL 17./Major histocompatibility complex (MHC) polymorphism is a major hindrance to transplantation success. Both minor and major antigen disparities between donor and recipient increase the risk of transplant rejection. This is thwarted by the administration of an immunosuppressive therapy that unspecifically affects all immune responses therefore increasing the risk of infections and cancers. Besides, this treatment does not seem to prevent chronic rejection.Recent studies have confirmed the existence of lymphocytes called regulatory T cells (Tregs), whose role is to maintain the general immune homeostasis and to protect the individual from autoimmune diseases.The classically described Tregs express constitutively the CD4 antigen, the alpha chain of the interleukin (IL)-2 receptor (CD25) and the transcription factor Foxp3. They represent 5 to 10% of total CD4+ T cells. Tregs are able to control alloreactive responses and were described to be responsible for the maintenance of allograft tolerance in mice. So far, the tolerogenic capacities of Tregs have been demonstrated either in mice treated with immunomodulatory antibodies (induced Tregs) or by adoptive co-transfer of Tregs and effector cells into lymphopenic mice. However, the latter has the disadvantage of not being able to distinguish the effect of Treg on lymphopenia-induced homeostatic proliferation from their effect on alloreactive responses. Herein, we show that Tregs play a crucial role in spontaneously accepted allografts in the absence of immunosuppressive therapy and in non-lymphopenic condition. Indeed, the depletion of the recipient’s Tregs through the administration of an anti-CD25 antibody enhances type Th1 and type-Th2 allogeneic responses, consequently triggering allograft rejection. However, the regulatory properties of Tregs are not unlimited. Indeed, we found that Tregs are unable to control allogeneic IL-17 production by memory CD4+ T cells and are even necessary for de novo Th17 differentiation. We conclude, therefore, that Tregs naturally present in the recipient play a critical role in protecting the allograft. Nevertheless, despite this context of regulation, IL-17-producing alloreactive T cells, beyond the control of Tregs, could mediate an alternative pathway of allograft rejection.Doctorat en Sciences médicalesinfo:eu-repo/semantics/nonPublishe

Severe auto-immune hemolytic anemia in a fingolimod-treated multiple sclerosis patient.

Journal ArticleSCOPUS: le.jinfo:eu-repo/semantics/publishe

Induction de tolérance: De la délétion à la régulation

info:eu-repo/semantics/publishe

Alloreactive IL-17 production escapes to FOXP3posTreg mediated suppression

info:eu-repo/semantics/nonPublishe

Chronic myeloid leukemia may no longer be a contraindication to lung transplantation

SCOPUS: le.jinfo:eu-repo/semantics/publishe

Targeted treatment options in mastocytosis

Mastocytosis refers to a heterogeneous group of disorders resulting from the clonal proliferation of abnormal mast cells and their accumulation in the skin (cutaneous mastocytosis when only in the skin, CM) or in various organs (systemic mastocytosis, SM). This leads to a wide variety of clinical manifestations resulting from excessive mediator release in CM and benign forms of SM (indolent SM, ISM) and from tissue mast cell infiltration causing multiorgan dysfunction and failure in more aggressive subtypes (aggressive SM, ASM, or mast cell leukemia). In addition, SM may be associated with hematological neoplasms (AHN). While treatment of ISM primarily aims at symptom management with anti-mediator therapies, cytoreductive and targeted therapies are needed to control the expansion of neoplastic mast cells in advanced forms of SM, in order to improve overall survival. Mast cell accumulation results from a gain-of-function mutation (mostly the D816V mutation) within the KIT tyrosine kinase domain expressed by mast cells and additional genetic and epigenetic mutations may further determine the features of the disease (ASM and AHN). Consequently, tyrosine kinase inhibitors and targeted therapies directed against the oncogenic signaling machinery downstream of KIT are attractive therapeutic approaches. A better understanding of the relative contribution of these genetic and epigenetic events to the molecular pathogenesis of mastocytosis is of particular interest for the development of targeted therapies and therefore to better choose patient subgroups that would best benefit from a given therapeutic strategy.SCOPUS: re.jinfo:eu-repo/semantics/publishe

An Unusual Case of Delayed Hemolytic Transfusion Reaction With Hyperhemolysis Syndrome Due to Anti-Jkb and Anti-Fya Alloantibodies.

Delayed hemolytic transfusion reaction (DHTR) is a complication appearing a few days to weeks due to alloimmunization following packed red blood cells (RBCs) transfusion, a pregnancy, or transplantation. Hyperhemolysis syndrome (HS) is a severe form of DHTR defined by a drop of hemoglobin to a level lower than before the transfusion, reflecting a destruction of the patient's own RBCs not presenting the targeted antigen as well as the transfused RBCs. Usually seen in sickle cell disease (SCD) patients, HS remains very rare in patients without a hematologic disorder. We report the case of an 82-year-old Caucasian woman who presented with a DHTR with HS after being transfused packed RBC twice in the context of rectal bleeding. The patient was not known for any hemoglobinopathy and did not have a history of massive transfusions nor multiple pregnancies putting her at risk of alloimmunization. Our patient developed anti-C, anti-Fya and anti-Jkb antibodies, known to be harmful antibodies. First line of treatment after avoidance of further transfusions is intravenous immunoglobulins for 3 to 5 days and high-dose corticosteroids. Exceptional in the non-SCD population, this complication should be recalled by clinicians as it can be fatal if not treated appropriately. We performed a review of the literature using the words "delayed hemolytic transfusion reaction" and "hyperhemolysis syndrome" for similar cases. Finally, we describe how to diagnose, manage, and prevent this potentially fatal complication, which is still underrecognized even within the SCD population.info:eu-repo/semantics/publishe

Recommendations on the use of ruxolitinib for the treatment of myelofibrosis

Objectives: Myelofibrosis (MF) is a severe disease, with decreased life expectancy and heavy symptom burden. Ruxolitinib is the only approved pharmacotherapy for the treatment of MF patients. In Belgium, ruxolitinib is only reimbursed for MF patients with splenomegaly for whom the disease is categorized as intermediate-2 or high risk. The improvement of symptoms without spleen volume reduction is not considered sufficient to continue treatment. The aim of this manuscript is to provide guidance for the safe and effective administration of ruxolitinib, considering the particularities of the Belgian reimbursement criteria. Methods: Our recommendations are based on a consensus reached during two meetings, where available data and observations derived from clinical experience were discussed. Results and discussion: We recommend changing the current Belgian reimbursement conditions to include the evaluation of disease-related symptoms along with splenomegaly to decide whether ruxolitinib treatment should be continued or not. Indeed, the decrease in disease-related symptoms seems to be an equally important parameter as the decrease in splenic volume in the evaluation of the response to ruxolitinib. We also advocate for the treatment with ruxolitinib of MF patients in lower-risk categories with severe disease-related symptoms, as this drug could greatly improve their quality of life. Optimization of the ruxolitinib dose is recommended to avoid an unnecessary decrease in platelet count or hemoglobin that may jeopardize treatment continuation. Conclusion: With the aim to optimize the treatment of MF patients, the Belgian regulation for ruxolitinib should be revised in terms of reimbursement criteria, dose titration, stopping rules, and patient follow-up.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Spectral domain optical coherence tomography findings in early deferoxamine maculopathy: Report of two cases

Purpose: To describe spectral domain optical coherence tomography features in two cases of early deferoxamine induced retinal toxicity. Methods: Two patients complained of sudden bilateral visual loss and dyschromatopsia. Both suffered from acute myelocytic leukemia with severe aplastic anemia and were treated with intravenous deferoxamine for 1 month. First ophthalmologic exploration and follow-up included fundoscopic examination, fluorescence angiography, fundus autofluorescence, and spectral domain optical coherence tomography. Results: Initially, both patients presented with a decreased visual acuity, inferior to 20/ 100. Fundus examination revealed a loss of transparency of the outer retina in the two cases. Autofluorescence pictures displayed hypoautofluorescence in the macular area, whereas fluorescein angiography unveiled an annular hyperfluorescence staining in the macular zone. Spectral domain optical coherence tomography showed a serous detachment of the neuroepithelium associated with photoreceptor outer segment elongation. Deferoxamine toxicity was immediately suspected and therapy promptly interrupted. One week later, both patients recovered visual acuity of 20/20 but retinal pigment epithelium (RPE) mottling was noticed in the macular areas. Spectral domain optical coherence tomography monitoring showed a progressive resolution of serous retinal detachment. Elongation of the photoreceptor outer segment disappeared but the RPE remained thickened, interrupted, and fragmented at different macular loci. Conclusion: Serous detachment of the neuroepithelium associated with photoreceptor outer segment elongation in the early stage of deferoxamine maculopathy is described for the first time. Early drug discontinuation allowed a fast resolution of the serous detachment but the typical RPE pigment mottling observed at the resolution phase was noticed 1 week later. Copyright ?by Ophthalmic Communications Society, Inc.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Surprising erythrocytosis resolution after myomectomy: myomatous erythrocytosis syndrome

Myomatous erythrocytosis syndrome (MES) is a rare gynaecological condition associated with the presence of a uterine fibroid and isolated polycythaemia. The main characteristic of MES is that haemoglobin returns to a normal level after removal of the myoma. MES is poorly known and still not fully understood. This case report describes the history of a patient with MES with surprising erythrocytosis resolution after myomectomy