Prophylactic Treatment with Fms-Like Tyrosine Kinase-3 Ligand after Burn Injury Enhances Global Immune Responses to Infection

Abstract

Severely burned patients are susceptible to infections with opportunistic organisms due to altered immune responses and frequent wound contamination. Immunomodulation to enhance systemic and local responses to wound infections may be protective after burn injury. We previously demonstrated that pretreatments with fms-like tyrosine kinase-3 (Flt3) ligand (Flt3L), a dendritic cell growth factor, increase the resistance of mice to a subsequent burn injury and wound infection by a dendritic cell-dependent mechanism. This study was designed to test the hypothesis that Flt3L administration after burn injury decreases susceptibility to wound infections by enhancing global immune cell activation. Mice were treated with Flt3L after burn injury and examined for survival, wound and systemic bacterial clearance, and immune cell activation after wound inoculation with Pseudomonas aeruginosa. To gain insight into the local effects of Flt3L at the burn wound, localization of Langerhans cells was examined. Mice treated with Flt3L had significantly greater numbers of CD25-expressing T cells and CD69-expressing T and B cells, neutrophils, and macrophages after, but not before, infection. Overall leukocyte apoptosis in response to infection was decreased with Flt3L treatment. Survival and local and systemic bacterial clearance were enhanced by Flt3L. Langerhans cells appeared in the dermis of skin bordering the burn wound, and further increased in response to wound infection. Flt3L augmented the appearance of Langerhans cells in response to both injury and infection. These data suggest that dendritic cell enhancement by Flt3L treatments after burn injury protects against opportunistic infections through promotion of local and systemic immune responses to infection.

Immunotherapy: A promising approach to reverse sepsis-induced immunosuppression

“…Flt3L is usually considered to act in synergy with other endogenous cytokines such as IL-7, IL-3 and IL-11 to stimulate B cell lymphopoiesis in vitro , with IL-12 in thymus to promote T cell development, and with IL-15 to promote NK cell development [143]. Flt3L has been shown to an effective dendritic cell growth factor and a large expansion of dendritic cells has been observed in healthy human volunteers [144], as well as mice [145] receiving Flt3L. Flt3L treatment causes a potent expansion of splenic dendritic cells, which enhances neutrophil antimicrobial functions and improves survival during burn injury and Pseudomonas aeruginosa sepsis, and the protective effect was sustained even with adoptively transferring Flt3L-treated dendritic cells [145, 146].…”

Accumulation of DC in Lamina Propria Induced by FMS-Like Tyrosine Kinase 3 Ligand Aggravates the Intestinal Inflammatory Response During Endotoxemia

“…However, after 24 h, all mice pretreated with Flt3L died, compared to 40% of vehicle-treated mice. [20,21]. Our initial hypothesis was that Flt3L pretreatment renders mice more resistant to challenge with gut bacteria during endotoxemia.…”

“…Their loss would profoundly inhibit their ability to clear the primary infection and lead to an increased propensity to bacterial translocation and secondary infections. Several investigators have reported that the enhancement of DC production could increase the resistance of mice to secondary infections [20][21][22][23], or even reverse endotoxin tolerance-related immunoparalysis [24]. Thus, we hypothesized that pre-enrichment of the LP DC pool would improve protective immunity to bacterial translocation and outcome in endotoxemic mice.…”

Enhancement of wound closure in diabetic mice by ex vivo expanded cord blood CD34+ cells

“…It has been reported that human skin keratinocytes and fibroblasts express Flt3-L [41]. Studies on the infection of burns in a mouse model showed that treatment with Flt3-L could lead to an enhancement of the dendritic cell number and functions, which in turn could stimulate neutrophil recruitment and function in the immune response to the infection [42][43][44]. IL-6 is mainly secreted by epidermal keratinocytes, while macrophages, Langerhans cells and fibroblasts in the dermis are the other sources in the skin [45,46].…”