Distinct phases in recovery of reconstituted innate cellular-mediated immunity after murine syngeneic bone marrow transplantation

Abstract

Defects in immune reconstitution after hematopoietic stem cell transplantation confer extreme infection risk on to the transplant recipient. Perturbations in adaptive immune reconstitution have been well characterized, yet defects in reconstituted innate cellular-mediated immunity remain largely unstudied. Recovery in innate effector cells was defined by using an established murine model of autologous bone marrow transplantation. Cytokine induction after cell culture and systemic stimulation with pathogen-associated molecular patterns was also measured for control, transplant-recipient, and irradiated-only animals. Early reconstitution (7 to 14 days) of donor-derived macrophages, dendritic cells, and polymorphonuclear cells was associated with recovery in interleukin (IL)-12p70 and IL-6 production. Later reconstitution (21 days) of natural killer cells was associated with interferon (IFN)-gamma recovery. Hence, splenocyte innate cellular-mediated immunity recovered to normal levels in cellularity and IL-12p70, IFN-gamma, and IFN-alpha production by 21 days after transplantation. In contrast, levels of systemic cytokine production from transplant-recipient and irradiated-only animals were preserved despite incomplete or absent hematopoietic reconstitution. These results suggest that innate immune responses to systemic inflammatory challenges are largely intact after autologous bone marrow transplantation, whereas local innate cellular-mediated immunity within reconstituting lymphoid organs may be impaired. The disparate effects of autologous hematopoietic stem cell transplantation on host immune function may translate to differences in susceptibility to local versus systemic infectious challenges.

Immune restoration following hematopoietic stem cell transplantation: an evolving target

“…That is, studies have shown that host cells including T cells 294 and DCs 50,53 are present in the early post transplant period. In addition, BM stromal and mesenchymal stem cells remain host in origin for years after successful donor-derived hematopoietic engraftment.…”

“…295,296 In what capacity these host cells influence donor-derived hematopoietic and immune recovery remains to be defined. However, these host-derived immune effector cells do contribute to inflammatory responses in the post transplant period; 53 and their presence has implications with respect to risk for relapse disease 297 and anti-microbial responses. 298 Therefore, further study is warranted to define if hostderived immune cells modulate effects on donor-derived hematopoiesis and immune recovery.…”

“…Unfortunately, a great void in the literature exists with respect to how reconstituted DCs function. 53 Following autologous PBSCT, reconstituted DC function has been shown to have significant antigen-presenting capacity. 43 However, such observations have been made using in vitro DC generated from precursor populations in the PB of transplant recipients.…”

Eicosanoid regulation of pulmonary innate immunity post-hematopoietic stem cell transplantation

“…There are some conflicting studies as to the functional ability of PMNs post-HSCT. Researchers found that reconstituted PMNs had diminished or impaired chemotaxis, superoxide production, and bactericidal activity for at least two months after allogeneic HSCT [5]. Similarly, impairment in chemotaxis, superoxide induction, and phagocytic function was found months to years post-transplant in PMNs from patients receiving autologous transplants [106].…”

“…Peripheral phagocytes and NK cells are the first cells to be reconstituted post-HSCT in human transplant recipients [5,61]. After the initial reestablishment of phagocytes, there is repopulation of early lymphoid cells responsible first for primitive and then for more specific functions, such as proliferation, helper activity, differentiation, cytokine production, and antibody synthesis [61].…”