Project name: Project category: Kind of research: Country: Principle investigator:

Natural Killer immunity during CMV infection in the context of lung transplantation

France Delphine Sauce
Status: Ongoing

Background : Lung transplantation remains the only curative therapeutic option of the end stage respiratory diseases such as cystic fibrosis, chronic obstructive pulmonary disease, pulmonary fibrosis. However, lung transplant mortality remains high (survival is 68% after one year post transplantation) and is mainly depending on acute and chronic rejection, and opportunistic infections like CMV infection. Before the CMV prophylaxis era, CMV infection could lead to very severe graft injuries. In solid organ transplantation, epidemiological associations have been established between the occurrence of acute and/or chronic rejection and CMV infection. However, the reason for this association remains unclear.
CMV establishes an asymptomatic although chronic infection in most immunocompetent subjects. Infection with this persistent virus is very common, reaching a prevalence of 60% in the middle aged population. Primary infection is associated with strong immune activation and inflammation. It is followed by a chronic phase of infection with persistent antigen exposure during which an equilibrium between viral replication and immune control is established. The immune response against CMV is characterized by massive expansions of CMV specific T lymphocytes, in particular CD8+, which exhibit a pro-inflammatory functional profile. Recently, new subsets of circulating cells have been described to be involved in the control of CMV, mainly γδ T cells and highly differentiated NK cells. This suggests that both adaptive and innate immunity may play a role in the surveillance of viral replication.
Our hypothesis is that in lung transplant recipients, there is an important expansion of cells responsive towards CMV following either CMV primary infection or reactivation. These cells can migrate into the graft and then generate local conditions favoring acute rejection, such as increased graft allogenicity due to infected cell lysis, and local inflammatory environment.

Methods: In order to test this hypothesis, we plan to perform a comprehensive study of CMV responsiveness in lung transplant recipient (n=46) followed in Foch Hospital (Paris). Longitudinal analysis of NK responses will be performed over 24 months after lung transplantation in peripheral blood, broncho-alveolar lavage (BAL) and lung tissues. Patients have been categorized according to the CMV serostatus of the donor/recipient pairs. All the samples and clinical data are available.
The methods used for the project are routinely performed in the lab, involving primarily flow cytometry based assays (surface or intra-cellular multi-parametric staining, cell sorting) focusing on the phenotype and the function (cytokine secretions, killing of targets…). We will be able to correlate the characteristics of NK cells with the occurrence of clinical events, such as CMV infection, rate and severity of acute rejection and rate of chronic rejection.

Objectives & Expected results: While anti-CMV T-cell immunity is important to prevent the development of CMV related disease, it could also have adverse effects at the level of the transplanted lungs, by affecting the balance between the transplant and its host towards acute rejection. Our aim is to get insights into the relationship between CMV infection and acute rejection, which is important to optimize the immunosuppressive and prophylactic treatments of transplanted patients.

Project amount (€): 53.000

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