Virginie De Wilde

The multiple facets of toll-like receptors in transplantation biology.

Toll-like receptors (TLRs) belong to a family of pattern-recognition receptors for microbial products and endogenous molecules released by stressed cells. Experimental studies show that TLRs are involved in the process of acute allograft rejection and that their activation can prevent transplantation tolerance. Herein, we review the expression of TLRs and the impact of TLR signaling in different cell types in grafted organs including antigen-presenting cells, T and B lymphocytes, epithelial and endothelial cells. We then discuss the involvement of TLRs in the different phases of the rejection phenomenon and the impact of TLR-mediated events on regulatory circuits which dampen alloimmune responses.

Interleukin 17–producing T helper cells in alloimmunity

Interleukin (IL) 17 is a proinflammatory cytokine already known to play a defense role against microbes and a pathogenic role in a number of autoimmune diseases. Although IL-17 can be produced by a variety of cells including neutrophils, CD8+, NK, and gamma-delta T cells, the concept of IL-17-secreting CD4+ T helper cells (Th17), distinct from Th1 and Th2, recently emerged. Herein, we discuss arguments in favor of a Th17-mediated alternative pathway of allograft rejection based on clinical and experimental observations drawn from the literature. We also discuss the complex interplays among regulatory T cells and Th17 cells in the allogeneic context.

IL-17 production elicited by allo-major histocompatibility complex class II recognition depends on CD25posCD4pos T cells.

Background. Interleukin (IL)-17 is involved in autoimmune inflammatory disorders and naturally occurring CD25pos regulatory T cells were shown to promote IL-17 synthesis. Because IL-17 is overproduced in certain types of allograft rejection, it is important to characterize the cells responsible for IL-17 synthesis and to define how IL-17 is regulated during alloimmune responses. Methods. Splenic CD4pos T cells were isolated from C57BL/6 mice and fractionated according to CD25 expression. T cells were stimulated by major histocompatibility complex class II-mismatched bone marrow-derived dendritic cells from bm12 mice, either immature or made mature by exposure to lipopolysaccharide. To track T cell populations, CD25negCD4pos and CD25posCD4pos were isolated from Thy1.1 and congenic Thy1.2 mice, respectively. Cell proliferation was quantified by CFSE dilution. IL-17-producing cells and FOXP3pos cells were enumerated by intracytoplasmic staining and cytokine levels in culture supernatants were measured by ELISA. Results. Addition of CD25posCD4pos T cells to CD25negCD4pos T cells inhibited IL-2, interferon-γ, and IL-13 production but promoted IL-17 synthesis on stimulation by allogenic immature DC. In this setting, IL-17 originated from CD25intCD4posFOXP3neg memory T cells, which depend on IL-2 to produce IL-17. Alloreactive CD25negCD4pos T cells were also induced to produce IL-17 when stimulated by mature DC in the presence of CD25highCD4posFOXP3pos T cells. Conclusions. We conclude that (1) the cellular source of IL-17 during an antiallo major histocompatibility complex class II response depends on the maturation status of allogenic DC, (2) whereas suppressing Th1 and Th2 cytokine synthesis, naturally occurring regulatory T cells, allow IL-17 production by alloreactive CD4pos T cells.

Endotoxin hyperresponsiveness upon CD4+ T cell reconstitution in lymphopenic mice: control by natural regulatory T cells

Natural CD4+CD25+ regulatory T cells (nTreg) have been shown to control graft‐versus‐host disease after hematopoietic stem cell transplantation (HSCT). Herein, we considered the possibility that the beneficial action of nTreg upon immune reconstitution in lymphopenic hosts involves dampening of the inflammatory response induced by bacterial products. We first observed that transfer of syngeneic CD4+CD25– T cells in RAG‐deficient mice dramatically enhanced release of inflammatory cytokines and associated pathology upon endotoxin injection. Interferon (IFN)‐γ produced by T cells undergoing homeostatic proliferation was shown to be involved in the endotoxin hyperresponsiveness induced by CD4+ T cell reconstitution. Co‐transfer of CD4+CD25+ nTreg with CD4+CD25– T cells inhibited the expansion of IFN‐γ‐producing T cells and reduced endotoxin responses in RAG–/– mice. We conclude that (1) CD4+ T cell reconstitution sensitizes lymphopenic hosts to endotoxin‐induced pathology and (2) nTreg prevent this process by limiting the emergence of IFN‐γ‐producing cells.

Clonal eosinophil and mast cell diseases: different in the same way?

Eosinophils and mast cells (MCs) come from the same pluripotent hematopoietic progenitor CD34+, CD117 + (KIT) cells and share common myeloid antigens such as CD33 and CD300a. Lineage restriction of these cell types is controlled by a similar network of transcription factors (e.g. GATA1 and PU-1), growth factors (stem cell factor and granulocyte macrophage colony stimulating factor, and cytokines (interleukin [IL]-5 and IL-3). Furthermore, factors produced by one cell type may have chemotactic, activation, growth, and survival effects on the other (e.g. histamine, IL-5, IL-6, IL-9, IL-33, chemokine ligand 5, and tumor necrosis factor). Systemic mastocytosis (SM) and myeloproliferative variant hypereosinophilic syndromes (HESn) are myeloproliferative neoplasms (MPN) that may present with an expansion of both cell types. However, they are separate clinical entities, associated with different symptoms, signs, and prognosis and, most of the time, a specific underlying tyrosine kinase (TK) abnormality. Very rarely, these molecular abnormalities may coexist [1], and in some debatable cases, a single molecular lesion is detected, but morphological and immunologic criteria for both entities are fulfilled. The resulting confusion has led investigators to develop practical tools to help distinguish between primitive eosinophilic versus MC neoplasms [2].

Microsatellite polymorphism in the heme oxygenase‐1 gene promoter is not associated with alcoholic liver disease severity

We thank Pesta and Burtscher for their comments on our study. In this article, we have demonstrated, for the first time, that 4 months of resistance (RES) or aerobic (AER) training are equally effective in reducing hepatic fat content among sedentary type 2 diabetes subjects with nonalcoholic fatty liver disease (NAFLD). This study was a subproject of the RAED2 Study, a randomized, controlled trial aimed at comparing the metabolic effects of RES and AER training in diabetic patients. Pesta and Burtscher hypothesized that in untrained overweight/ obese subjects with little experience in exercise, RES training would be unable to induce the specific adaptations characteristic of this exercise modality, and that this, in turn, might explain why the results of AER and RES training were similar. We agree that, in untrained subjects, there may be some overlap between the effects of AER and RES training, and that the fullblown effects of these different exercise modalities can be only appreciated when sustained high-intensity training is performed, as occurs in athletes. Nonetheless, the latter would not be an appropriate model for assessing the effects of these training modalities on hepatic fat accumulation of sedentary subjects with type 2 diabetes, which was the aim of our study. Moreover, as reported previously, in our study, peak oxygen uptake improved after training in both groups, but to a greater extent in the AER group, whereas increased strength was found only in the RES group. In addition, lean mass of the limbs significantly increased in the RES group, but not in the AER group. These findings clearly indicate that the stimulus was quite different between the two protocols. These differences were guaranteed through a careful supervision of exercise sessions as well as a progressive increase of workload. In particular, as concerns the RES group, workload was gradually increased to 70%-80% 1-RM, with the weight being adjusted approximately every 2 weeks to match the progress of the subjects. With regard to baseline data, there were not statistically significant differences between groups. Overall, most type 2 diabetes patients are sedentary and have no experience with exercise programs. The clinical message that we were able to give is that exercise alone can provide benefit for NAFLD management in these patients, and that, after 4 months of training, RES exercise is as effective as AER exercise in reducing hepatic fat content in these subjects. Future research should address this important issue in the long term.

A Belgian consensus protocol for autologous hematopoietic stem cell transplantation in multiple sclerosis

Multiple sclerosis is considered to be an immune mediated inflammatory disorder of the central nervous system. It mainly affects young, socioeconomic active patients. Although our armamentarium for this disease has significantly evolved in recent years some patients remain refractory to conventional therapies. In these cases, autologous hematopoietic stem cell transplantation can be considered as a therapeutic option. Decreasing morbidity, mortality, and increasing patient awareness have led to rising inquiry by our patients about this treatment option. With the aim of a standardized protocol and data registration, a Belgian working party on stem cell therapy in multiple sclerosis was established. In this paper, we report the consensus protocol of this working party on autologous hematopoietic stem cell transplantation in multiple sclerosis.