Immunoregulatory T Lymphocytes Subtypes and Haematopoietic Stem Cell Transplantation (HSCT)

Allogeneic Hematopoietic Stem Cell Transplantation for Hematological Malignancies

Allogeneic hematopoietic stem cell transplantation,, Immunoregulatory T lymphocytes,, acute graft versus host disease

The purpose of this study is to confirm that invariant NKT lymphocytes (iNKT) reconstitution in recipient and in the graft content can predict the outcome of human allogeneic HSCT and to set up an algorithm for clinical practice that would allow the prediction of acute GVHD risk according to the quantity and functionality

Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative treatment in most haematological malignancies. However, its anti-tumor effect (GVT) is often associated with the development of a graft versus host disease (GVHD) and impaired immune anti-infectious responses. The predictive and protective features of iNKT cells on the development of acute GVHD (aGVHD) are not or poorly known in humans and their mechanisms of action, in particular their potential interactions with the other regulatory effectors and immune actors of the allogeneic response, remain to be explored. Our project aims, first, to show that the post-transplant reconstitution and/or the content of the graft in some immunoregulatory T lymphocytes can early predict the post-transplant clinical outcome and, second, to explore the underlying immunological mechanisms. For that, we propose to analyse, in homogeneous cohorts of allografted patients and their donors, the levels of iNKT cells and other cell populations implicated in the allogeneic immune response (Tregs, mucosa-associated invariant T (MAIT) cells, delta gammaT and anti-viral specific T cells) and correlate the results to the post-transplant outcome (GVHD, infections, relapse, survival). This study will be performed in a cohort of 80 adult allografted patients in four transplant departments in Paris (hospitals of Necker, Saint Antoine, Saint Louis and La Pitié Salpétrière) and in a cohort of 60 allografted paediatric patients (Robert Debré hospital in Paris). Sequential blood samples of patients will be drawn to monitor the immune reconstitution of the different lymphocyte populations of interest by flow cytometry and perform functional studies on iNKT (ex vivo expansion capacities and cytokine production). These analyses will be also performed in the corresponding donors from blood samples collected before the collection process and from the grafts (obtained by the cell therapy departments of Necker, La Pitié Salpétrière and Saint Louis hospitals). In addition, we plan to analyse the effect of, and the mechanisms by which, human cluster of differentiation 4 (CD4) CD4- and CD4+ iNKT cells might control the allogeneic response in vitro, particularly via their potential interactions with dendritic cells and Tregs. According to the results of the mechanistic studies, we will test the effect of human subtypes of iNKT cells on the GVH/GVL affects in a preclinical humanized mouse model of allogeneic HSCT. The clinical and biological data will be anonymously entered in the electronic case report by the investigators up to 3 years post transplant.

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