Defective Pulmonary Innate Immune Responses Post-Stem Cell Transplantation; Review and Results from One Model System

Abstract

Infectious pulmonary complications limit the success of hematopoietic stem cell transplantation (HSCT) as a therapy for malignant and non-malignant disorders. Susceptibility to pathogens in both autologous and allogeneic HSCT recipients persists despite successful immune reconstitution. As studying the causal effects of these immune defects in the human population can be limiting, a bone marrow transplant (BMT) mouse model can be used to understand the defect in mounting a productive innate immune response post-transplantation. When syngeneic BMT is performed, this system allows the study of BMT-induced alterations in innate immune cell function that are independent of the confounding effects of immunosuppressive therapy and graft-versus-host disease. Studies from several laboratories, including our own show that pulmonary susceptibility to bacterial infections post-BMT are largely due to alterations in the lung alveolar macrophages. Changes in these cells post-BMT include cytokine and eicosanoid dysregulations, scavenger receptor alterations, changes in micro RNA profiles, and alterations in intracellular signaling molecules that limit bacterial phagocytosis and killing. The changes that occur highlight mechanisms that promote susceptibility to infections commonly afflicting HSCT recipients and provide insight into therapeutic targets that may improve patient outcomes post-HSCT.

Inhibition of Neutrophil Extracellular Trap Formation after Stem Cell Transplant by Prostaglandin E2

“…We were only able to obtain one BAL fluid sample with sufficient neutrophils for analysis, but BAL fluid-derived cells behaved similarly to peripheral-blood-derived cells from other HSCT patients in responses to EP2 antagonists ( Figures 5A and 5B). Although it is possible that other changes in the lung after BMT (e.g., elevated IL-6 and granulocyte-macrophage colony-stimulating factor; decreased tumor necrosis factor-a, IFN-g, and leukotrienes) (24,33,41,42) or other COX-2 effectors (e.g., thromboxane and prostacyclin) may also serve roles in regulating NETosis, our studies prove that PGE 2 signaling limits NETosis. Because PGE 2 -EP2 or PGE 2 -EP4 intracellular signaling relies on PKA and/or Epac (43), we explored the contribution of both pathways in NET regulation.…”

“…In A, n = 6/group for media and PMA stimulations and n = 3/group for S. pneumoniae stimulation; in B, n = 3/group; in D, the n = 15/group. functional defects in alveolar macrophages and neutrophils that occur after BMT (25,26,33). Thus, we focused on the effects of PGE 2 on NETosis.…”

Prostaglandin E 2 as a Regulator of Immunity to Pathogens

“…Interestingly, PGE 2 -mediated activation of PKA/EPAC was reported to downregulate NET release (Domingo-Gonzalez, et al, 2016; Shishikura, et al, 2016). This is of high importance in hematopoietic stem cell transplanted (HSCT) patients who have been reported to harbor high levels of PGE 2 in the serum and bronchoalveolar lavage fluid (Ballinger, et al, 2007; Cayeux, et al, 1993; Coomes, Hubbard, & Moore, 2011; Domingo-Gonzalez, et al, 2016; Domingo-Gonzalez & Moore, 2013). Neutrophils from these patients are unable to induce NET release upon phorbol myristate acetate stimulation or bacterial encounter (Domingo-Gonzalez, et al, 2016).…”

Innate Immunity Post-Hematopoietic Stem Cell Transplantation: Focus on Epigenetics

“…Infectious complications arise throughout the different phases of reconstitution. In the context of transplantation, there are three phases: 1) the pre-engraftment (0–30 days post-transplant), 2) the early post-engraftment (30–100 days post-transplant), and 3) the late post-engraftment phase (beyond 100 days post-transplant) [8, 12–14]. Not surprisingly, transplant patients in the pre-engraftment phase are afflicted with pulmonary bacterial and viral infections.…”