Immunologie | EPFL Graph Search

L'immunologie est la branche de la biologie qui s'occupe de l'étude du système immunitaire. Apparu très tôt au cours de l'évolution, ce système a évolué pour distinguer le non-soi du soi. Les réactions de défense de l'organisme face à un organisme pathogène — quelle que soit la nature de celui-ci, virus, bactéries, champignons ou protozoaires. Les maladies auto-immunes, les allergies et le rejet des greffes forment l'aspect médical de cette science. Les mécanismes de synthèse et de maturation des anticorps, d'activation du système du complément, la mobilisation et la coordination des cellules de défense, en forment l'aspect fondamental et mécanistique. Histoire Antiquité Les plus anciens témoignages connus d’observations d’ordre immunologique datent de 430 lorsque l’historien Thucydide relata un épisode de « peste ». À cette date, pendant l’épidémie de fièvre typhoïde qui sévit à Athènes durant la guerre du Péloponnèse, Thucydide nota que seules les personne

Engineering the Extra Domain A of fibronectin as a vaccine adjuvant and study of its role in tissue regeneration

Ziad Julier

The extracellular matrix (ECM) protein fibronectin (FN) is a remarkably multifaceted molecule, including numerous fibronectin type III (FNIII) repeats carrying out different functions, which despite being extensively studied for over thirty years still presents certain functions that remain incompletely elucidated. The alternatively spliced FN variant containing the extra domain A (FNIII EDA), located between FNIII 11 and FNIII 12, is expressed in sites of injury, chronic inflammation, and solid tumors. Although its function is not well understood, FNIII EDA is known to agonize Toll-like receptor 4 (TLR4) and appears to be involved in the progression of different skin diseases while studies also suggest that FNIII EDA is involved in tissue repair. The aim of this thesis is thus to better understand some of the immunological and regenerative functions of FNIII EDA and to translate these findings to develop new vaccination strategies based on endogenous proteins. One important task in vaccinology is to develop delivery strategies by which to present antigen, along TLR agonists, so as to induce a desirable adaptive immune response. The use of TLR agonists is associated with sometimes severe constraints and concerns about safety, causing inflammatory responses. Thus, the development of safe and effective vaccines with fewer side effects is a strong need and requires the development of new adjuvants with a correct balance between a strong activation of the immune system and a low toxicity for the patient. Here, by producing various FN fragments containing FNIII EDA, we show that the immunological activity of FNIII EDA depends on its local intramolecular context within the FN chain. N-terminal extension of the isolated FNIII EDA with its neighboring FNIII repeats enhanced its activity in agonizing TLR4, while C-terminal extension abrogated it. In addition, we reveal that an elastase 2 cleavage site is present between FNIII EDA and FNIII 12. Moreover, as FNIII EDA is naturally present within the ECM, we incorporated FNIII EDA bound in a fibrin matrix to mimic the in vivo situation and create an adjuvant-rich microenvironment. Such matrices were shown to induce functional cytotoxic CD8+ T cell responses in two murine cancer models. Furthermore, combinations of specific TLR-agonists have the ability to synergize to induce immune responses that are greater than the sum of their individual effect. Hence, we demonstrate that combination of the TLR9 agonist CpG with FNIII EDA synergizes to induce an efficient immune response while keeping the dose of the toxic CpG at a minimum. Here, the combination of both adjuvants induced a potent immune response sufficient to slow down tumor growth in a murine tumor model as well as to break immune tolerance to eradicate circulating hepatitis B virus (HBV) in a transgenic HBV mouse model. Finally in the last part of this thesis we revealed that FNIII EDA is a growth factor binding domain of FN, with a strong affinity for the platelet-derived growth factor-AA (PDGF-AA). We also demonstrated that FNIII EDA and PDGF-AA have together the ability to enhance fibroblasts proliferation and differentiation into myofibroblasts. In addition, we explored the effects of fibrin matrices functionalized with variants of FNIII EDA on wound closure.

EPFL2016

Interleukin-2 mastering regulation in cancer and autoimmunity

Livan Bladimir Alonso Sarduy, Ricardo Pérez Suárez

Autoimmunity and tumor immunity evolved as two distinct arenas in immunological research. However, the identification of self-antigens as the major components of malignant cells may define a central role for autoimmunity in cancer control tuned by peripheral immunoregulatory mechanisms avoiding self-aggression. Emerging evidence documents a triple antagonistic role of interleukin-2 (IL-2) in vivo promoting survival, apoptosis, and the generation of regulatory T cells. We have found that IL-2 administration reduces the clinical course of experimental autoimmune encephalomyelitis and enhances immunoregulation in tumor-bearing mice. However, actively induced anti-IL-2 antibodies restore the response to nominal antigens in tumor-induced immunosuppressed host and induced therapeutic effect in transplantable and chemically induced tumors. It is suggested that IL-2 may contribute dynamically to the maintenance of natural immunological tolerance, preventing pathological autoimmunity, but may affect antitumor immunity. Cancer research has gained from autoimmunity understanding that tumor escape strategies include the natural mechanisms of immune tolerance and the ways to imbalance the peripheral regulatory mechanisms. Interestingly, therapeutic manipulations of immunoregulation have limited antitumor effects, although promoting collaterally infrequent autoimmune diseases. It may suggest that tumors may reinforce tolerance to protect themselves from the immune attack, a process that may involve dynamically various mechanisms including IL-2. Understanding this acquired experience from tumors may help utilize them to revert the immunopathology in autoimmune diseases.

2007

The TLR4 Agonist Fibronectin Extra Domain A is Cryptic, Exposed by Elastase-2; use in a fibrin matrix cancer vaccine

Alexandre de Titta, Jeffrey Alan Hubbell, Laura Jeanbart, Ziad Julier, Mikaël Martino

Fibronectin (FN) is an extracellular matrix (ECM) protein including numerous fibronectin type III (FNIII) repeats with different functions. The alternatively spliced FN variant containing the extra domain A (FNIII EDA), located between FNIII 11 and FNIII 12, is expressed in sites of injury, chronic inflammation, and solid tumors. Although its function is not well understood, FNIII EDA is known to agonize Toll-like receptor 4 (TLR4). Here, by producing various FN fragments containing FNIII EDA, we found that FNIII EDA's immunological activity depends upon its local intramolecular context within the FN chain. N-terminal extension of the isolated FNIII EDA with its neighboring FNIII repeats (FNIII 9-10-11) enhanced its activity in agonizing TLR4, while C-terminal extension with the native FNIII 12-13-14 heparin-binding domain abrogated it. In addition, we reveal that an elastase 2 cleavage site is present between FNIII EDA and FNIII 12. Activity of the C-terminally extended FNIII EDA could be restored after cleavage of the FNIII 12-13-14 domain by elastase 2. FN being naturally bound to the ECM, we immobilized FNIII EDA-containing FN fragments within a fibrin matrix model along with antigenic peptides. Such matrices were shown to stimulate cytotoxic CD8(+) T cell responses in two murine cancer models.

Nature Publishing Group2015

Engineering the Extra Domain A of fibronectin as a vaccine adjuvant and study of its role in tissue regeneration

Ziad Julier

EPFL2016