Patil 2015 Abstract MiPschool Greenville 2015

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Impaired adaptive immune system function following burn wound infection and evaluation of anti-PD-L1 antibody as an immunotherapeutic agent.

Link:

Patil NK, Bohannon J, Luan L, Guo Y, Sherwood E (2015)

Event: MiPschool Greenville 2015

Burn patients are at increased risk of developing wound infection and sepsis leading to multi-organ failure and death [1]. Previous studies show that T cell dysfunction and low absolute lymphocyte counts are major contributing factors to increased mortality in non-burned septic patients [2]. Although impaired antimicrobial immunity has been described in burn patients, the changes in adaptive immunity after burn injury and infection have not been investigated. We used a clinically relevant mouse model of burn wound infection to assess the adaptive immune system function.

A 35% TBSA full thickness burn was induced and the wound was infected with Pseudomonas aeruginosa on day 4 post-burn. Lymphocyte, macrophage and dendritic cell counts and phenotype in spleen and wound draining lymph nodes were characterized by flow cytometry.

We observed a significant decline (>80%) in blood absolute lymphocyte count and CD4+ and CD8+ T cell counts in the spleen and burn-draining lymph nodes of wound infected mice (WI) as compared to non-infected burn mice (see figure). WI also lead to a significant decrease in the expression of the co-stimulatory receptor CD28 on both CD4+ and CD8+ cells in spleen and lymph nodes. PD-1 expression was not affected. Dendritic cell counts were significantly decreased on day 2 post WI in the spleen (3x106 vs 4x106 in sham) and in lymph nodes (2x105 vs 6x105 in sham). WI also lead to a significant decrease in F4/80+ macrophage cell counts (48x105 vs 81x105); decrease in expression of MHCII on dendritic cells (29 vs 49 %); and an increase in the expression of PD-L1 on dendritic cells (31 vs 23%), macrophages (25 vs 10%) and Ly6C+ inflammatory monocytes (19 vs 11%) in the spleen, as compared to control. These changes were associated with significant kidney and liver injury and approximately 75 % mortality at day 3 after WI. PD-L1 is an inhibitory ligand expressed on the antigen presenting cells which interacts with PD-1 receptor on T lymphocytes and downregulate their function [3]. Importantly, treatment of wound infected mice with anti-PD-L1 antibody (50 µg, IP) every other day, starting one day before burn injury improved 7 day survival by approximately 30%.

We show that adaptive immune system functions are impaired following burn injury and wound infection and associated with a decrease in host resistance to infection. Anti-PD-L1 antibody might have therapeutic benefit in prevention and/or treatment of burn wound associated sepsis.


Labels: Pathology: Sepsis, Other 

Organism: Mouse 




Event: Poster 


Affiliations

Dept Anesthesiology, Vanderbilt Univ Med Center, Nashville, TN, USA. - naeem.patil@vanderbilt.edu

Figures

MiPschool2015Greenville Patil Figure1.jpg
MiPschool2015Greenville Patil Figure2.jpg












References and acknowledgements

  1. Mann EA, Baun MM, Meininger JC, Wade CE (2012) Comparison of mortality associated with sepsis in the burn, trauma, and general intensive care unit patient: a systematic review of the literature. Shock 37:4-16.
  2. Unsinger J, Burnham CA, McDonough J, Morre M, Prakash PS, Caldwell CC, Dunne WM Jr, Hotchkiss RS (2012) Interleukin-7 ameliorates immune dysfunction and improves survival in a 2-hit model of fungal sepsis. J Infect Dis 206:606-16.
  3. Zhang Y, Zhou Y, Lou J, Li J, Bo L, Zhu K, Wan X, Deng X, Cai Z (2012) PD-L1 blockade improves survival in experimental sepsis by inhibiting lymphocyte apoptosis and reversing monocyte dysfunction. Critical care 14:R220.