CD28 antagonists in autoimmune renal diseases – CAARD

Peripheral tolerance is an equilibrated system, a fine balance between pathogenic effector T cells (Teff) and regulatory T cells (Treg) aimed at controlling immune responses. Autoimmune diseases (AID) occur when this balance leans to autoreactive cells leading to the loss of tolerance towards one or several autoantigens. For yet undetermined reasons, AID frequently affect the kidneys. Systemic lupus erythematous (SLE) (i.e. lupus nephritis (LN)) and antineutrophil cytoplasm antibodies (ANCA)-vasculitis (AAV) are two prototypic AID which frequently (30-80%) induces severe renal damage. Both diseases arise from a loss of tolerance towards autoantigens: nucleic acids and nucleoproteins in the case of SLE and myeloperoxidase (MPO) and proteinase 3 (Pr3), two enzymes of neutrophils and monocytes, in the case of AAV. Current treatment of these two renal disorders consist mainly in non specific immunosupression (such as cyclophosphamide) and high-dose steroids, which are associated to high morbidity and mortality. Since these treatments do not specifically target the autoreactive component of the immune system, and importantly, also suppress the regulatory pathways, they usually have a transient impact on the course of AAV and LN, with significant numbers of patients experiencing disease relapse, requiring re-treatment. Innovative treatment strategy that restore the Teff/Treg equilibrium are crucially needed in patients with LN and AAV.
Our group has developed a “first-in-class” drug, an anti-CD28 antagonist. The latter modulates T cells costimulation pathways. Anti-CD28 antagonist inhibits CD28/CD80-86 interactions and thus the activation of Teff while allowing the CTLA4/CD80-86 interactions and thus the generation of Treg. It has been successfully used in an animal (primate) model of renal allotransplantation and is an ideal candidate for the optimal treatment, and potentially the cure, of AID affecting the kidney, such as LN and AAV, through the restoration of a balanced Teff/Treg ratio.
The aim of this project is to test the anti-CD28 antagonist in two animal models of LN and AAV. NZB/NZM (F1) mice are a well-established spontaneous model of LN. The anti-CD28 antagonist will be tested as a preventive (before the onset of LN) as well as a curative treatment strategy for LN. The efficiency of anti-CD28 antagonist will be assessed based on the development or worsening of proteinuria, on renal pathology features (inflammation, necrosis, immune deposits), on the analysis of T and B cells subtypes (Treg, Teff, autoreactive T and B cells) in the circulation and in the kidney as well as on mice survival.
For AAV, anti-CD28 antagonist will be tested in a widely used model of MPO-/- mice immunized with MPO and who develop renal features similar to those noted in human AAV. The efficiency of anti-CD28 antagonist will be assessed based on renal pathology features (inflammation, necrosis), and on the analysis of T and B cells subtypes (Treg, Teff, autoreactive T and B cells) in the circulation and in the kidney .
Establishing anti-CD28 antagonist as an innovative treatment in AID affecting the kidney will represent a breakthrough in the management of patients with these disorders. The restoration of a tolerance towards the autoantigens involved in the pathogenesis of these diseases may lead to the cure of AID.