ANTI-CD69 MAB TREATMENT INCREASES THE CAPACITY OF NK CELLS TO ELIMINATE HYPER-REACTIVE ALLOGENIC T CELLS AND PREVENTS ACUTE GRAFT VERSUS HOST DISEASE
Author(s): ,
Katerina Tsilingiri
Affiliations:
Centro Nacional de Investigaciones Cardiovasculares,Madrid,Spain
,
Marta Relano
Affiliations:
Centro Nacional de Investigaciones Cardiovasculares,Madrid,Spain
,
Antonio Balas
Affiliations:
Hospital Universitario de la Princesa
,
Valle Gómez García de Soria
Affiliations:
Hospital Universitario de la Princesa
,
Yaiza Pérez García
Affiliations:
Hospital Universitario de la Princesa
,
Cecilia Muñoz-Calleja
Affiliations:
Hospital Universitario de la Princesa,Madrid,Spain
Pilar Martin
Affiliations:
Centro Nacional de Investigaciones Cardiovasculares,Madrid,Spain
(Abstract release date: Jun 8, 2017) EHA Learning Center. Tsilingiri K. Jun 25, 2017; 183933
Katerina Tsilingiri
Katerina Tsilingiri
Login now to access Regular content available to all registered users.

Access to EHA Members only content is an EHA membership benefit.
Click here to join EHA or renew your membership here.


Abstract
Discussion Forum (0)
Rate & Comment (0)

Abstract: LB2603

Type: Late Breaking Oral Session

Presentation during EHA22: On Sunday, June 25, 2017 from 11:45 – 12:00

Location: Hall A

Background
Hematopoietic stem cell transplantation remains the best therapeutic option for blood malignancies. Acute graft versus host disease (aGvHD) is one of the main potentially fatal complications of this treatment 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 tumour cells more effectively than WT NK cells.

Aims
We wished 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.

Methods
We took advantage of a fully allogenic aGvHD mouse model in which wild type (WT) or CD69-/- BALBc mice were lethally irradiated and reconstituted with C57/BL6 HSCs and naïve T cells. Results were confirmed by in vivo killing assays as well as by use of CD69 neutralizing antibodies. Mouse strains deficient in T cells, B cells and NK cells were used to establish the NK cells as the population responsible for the observed phenotype. Mass cytometry was employed for extensive phenotyping of WT and CD69-/- NK cells and RNAseq analyses were used to elucidate the molecular mechanisms implicated.

Results
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. Further, 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 conditiong and transplant, and could be targeted with anti-CD69 mAb to avoid clonal expansion of highly reactive donor T cells.

Conclusion
NK cells treated with anti-CD69 mAb show 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.

Session topic: 21. Stem cell transplantation - Experimental

Keyword(s): Allogeneic stem cell transplant, Graft-versus-host disease (GVHD), NK cell

Code of conduct/disclaimer available in General Terms & Conditions