A novel approach to improve immune effector responses post transplant by restoration of CCL21 expression

Abstract

Chemotherapy or chemoradiotherapy conditioning regimens required for bone marrow transplantation (BMT) cause significant morbidity and mortality as a result of insufficient immune surveillance mechanisms leading to increased risks of infection and tumor recurrence. Such conditioning causes host stromal cell injury, impairing restoration of the central (thymus) and peripheral (spleen and lymph node) T cell compartments and slow immune reconstitution. The chemokine, CCL21, produced by host stromal cells, recruits T- and B-cells that provide lymphotoxin mediated instructive signals to stromal cells for lymphoid organogenesis. Moreover, T- and B-cell recruitment into these sites is required for optimal adaptive immune responses to pathogens and tumor antigens. Previously, we reported that CCL21 was markedly reduced in secondary lymphoid organs of transplanted animals. Here, we utilized adenoviral CCL21 gene transduced dendritic cells (DC/CCL21) given by footpad injections as a novel approach to restore CCL21 expression in secondary lymphoid organs post-transplant. CCL21 expression in secondary lymphoid organs reached levels of naïve controls and resulted in increased T cell trafficking to draining lymph nodes (LNs). An increase in both lymphoid tissue inducer cells and the B cell chemokine CXCL13 known to be important in LN formation was observed. Strikingly, only mice vaccinated with DC/CCL21 loaded with bacterial, viral or tumor antigens and not recipients of DC/control adenovirus loaded cells or no DCs had a marked increase in the systemic clearance of pathogens (bacteria; virus) and leukemia cells. Because DC/CCL21 vaccines have been tested in clinical trials for patients with lung cancer and melanoma, our studies provide the foundation for future trials of DC/CCL21 vaccination in patients receiving pre-transplant conditioning regimens.

Stem cell transplantation impairs dendritic cell trafficking and herpesvirus immunity

“…While the numbers of Th17 cells are comparable between normal and BMT mice in the dLNs, the Th17 cells of BMT mice make up a larger percentage of the population than those in non-BMT mice ( Figure 3B), further confirming a Th17-skewed response. It has been previously reported that both allogeneic and congeneic BMT reduces steady state cellularity in LNs after immune reconstitution and that BMT mice generate poor responses to bacterial and viral infections (19)(20)(21). Similarly, we also found that there is about a 3-fold reduction in total cell numbers in BMT lung dLNs at 7 dpi, with significantly fewer mDCs, CD4 + Th cells, CD8 + T cells, and B cells in the BMT dLNs ( Figure 3C).…”

“…It has been long recognized that the dLNs are small and disorganized in BMT recipients, and BMT mice generate poor responses to bacterial and viral infections (19)(20)(21)62). The levels of CCL21 protein in dLN stroma have previously been reported to be reduced in BMT mice at steady-state (19,21), but we did not detect such a reduction of Ccl21 at the transcription level ( Figure 4B). A transient downregulation of chemokine production within dLNs was observed in both non-BMT and BMT dLNs at 7 dpi, which has been reported to help orchestrate local cellularity and minimize competition for space and resources in activated lymphoid tissues (63).…”

“…DCs, a potent population of professional antigen-presenting cells (APCs) that activate and define T cell responses, reconstitute rapidly after transplant but with prolonged skewing of cell subsets (16). Furthermore, SCT conditioning damages the fibroblastic reticular cells and their expression of CCL21 in secondary lymphatic organs (19)(20)(21). CCL21 is essential for lymph nodes (LNs) to recruit naive T cells (22) and DCs (23).…”

Trial watch: dendritic cell vaccination for cancer immunotherapy

“…298 Stefanski et al (from University of Minnesota, Minneapolis, Minnesota, USA) pulsed DCs geneticallyengineered to overexpress CCL21 with TAAs, and reported the induction of efficient anticancer immunity in mouse models of leukemia. 299 Van Woensel et al (from KU Leuven, Leuven, Belgium) found that combining DC-based vaccines with the intranasal administration of chitosan nanoparticles loaded with small interfering RNAs targeting galectin 1 (LGALS1) drives robust tumor-targeting immune responses in a murine model of orthotopic glioma, correlating with dramatic changes in the tumor microenvironment in favor of M1polarized macrophages and effector T cells. 300 Huang et al…”

Laminarin Promotes Immune Responses and Normalizes Glutamic Oxaloacetic Transaminase and Glutamic Pyruvic Transaminase Levels in Leukemic Mice In Vivo

“…Numerous studies have focused on finding or developing novel therapeutic strategies or agents for such patients. Improving immune responses to mediate protection against leukemia (7,8) is needed. There is also focus on finding and improving immune responses from natural products.…”