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Preclinical data on the optimization of hematopoietic stem cell transplantations

Acute graft versus host disease (aGvHD) is one of the main potentially fatal complications of hematopoietic stem cell transplantation (HSCT) with an incidence as high as 50%. The NK cell population has been extensively studied as a potential target for treatments, as these cells have the capacity to potentiate the graft versus leukemia effect with a minimum risk for graft versus host reactions. Indeed, the abundance of circulating NK cells has been inversely correlated with the probability to develop aGvHD.

CD69 is a C-type lectin expressed on the surface of certain immune cell progenitors as well as activated mature leukocytes. CD69-/- NK cells were previously shown to eliminate tumor cells more effectively than wild type (WT) NK cells. To examine whether CD69-/- NK cells would have a higher cytolytic capacity against activated allogenic T cells and whether this would lead to successful aGvHD prevention, a fully allogenic aGvHD mouse model in which WT or CD69-/- BALBc mice were lethally irradiated and reconstituted with C57/BL6 hematopoietic stem cells and naïve T cells was examined.

CD69-/- mice were highly resistant to aGvHD and significantly more efficient at eliminating hyper-reactive allogenic T cells in vivo. This phenotype was reproduced in WT mice treated with a CD69 neutralizing monoclonal antibody during disease induction. Mass cytometry analyses showed that NK cells lacking CD69 expression upregulate the Ly49D and Ly49G2 receptors, responsible for self/non-self discrimination. In addition, the expression of inhibitory receptors such as CD94/NKG2A was downregulated in CD69-/- NK cells. Finally, in vivo data and RNAseq analyses indicated that CD69-/- NK cells are resistant to apoptosis. Preliminary data on NK cell chimerism from HSCT patients indicate that host NK cells can persist shortly after conditioning and transplant, and could be targeted with anti-CD69 mAb to avoid clonal expansion of highly reactive donor T cells.

In conclusion, NK cells treated with anti-CD69 mAb have a higher capacity to eliminate hyper-reactive allogenic T cells and confer resistance to aGvHD. This data could pave the way for novel therapeutic strategies to optimize allogenic HSCT.



Tsilingiri K, Balas A, Muñoz-Calleja C, et al.Anti-CD19 mAb treatment increases the capacity of NK cells to eliminate hyper-reactive allogenic T cells and prevents acute graft versus host disease. EHA 2017, oral presentation, abstract LB2603


Speaker Pilar Martin


Pilar Martin, MD, Spanish national center for cardiovascular research, Madrid, Spain


See: Keyslides


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