Longitudinal immune profile reveals reduced function of pro-inflammatory monocytes with age following kidney transplantation.

Toxicity of immunosuppression, notably the risk of infection, increases with age. However, the dynamic changes in innate immune response following transplantation are unclear. Based on recent observations, we hypothesized that pro-inflammatory capacity would decrease with age. We analyzed approximately 300 PBMC samples collected longitudinally in 45 de novo, adult kidney recipients and performed detailed phenotypic and functional profiling of monocytes and T cell subsets. Inflammatory response to TLR4 stimulation and indirect allostimulation using mismatched HLA peptides were assessed. In patients aged ≥56 years, TNF-α production by intermediate monocytes was similar to that in younger patients early posttransplant, but diminished substantially later. Adjusted analyses suggested that this was not attributable to confounding factors. In contrast, the alloimmune response to HLA peptides measured by IFN-γ in CD4+ T cells and TNF-α in monocytes was stable over time, but was low in older recipients. Measurement of CD80-86 surface expression revealed no signal for a lower costimulation capacity of APCs. These results suggest that older recipients have a reduced function of their innate pro-inflammatory immune cells posttransplant while maintaining a stable, low alloimmune response over time. The effect of reduced immunosuppressant doses on preventing this phenomenon needs to be clarified.

Plasmodium falciparum sexual parasites develop in human erythroblasts and affect erythropoiesis.

Plasmodium falciparum gametocytes, the sexual stage responsible for malaria parasite transmission from humans to mosquitoes, are key targets for malaria elimination. Immature gametocytes develop in the human bone marrow parenchyma, where they accumulate around erythroblastic islands. Notably though, the interactions between gametocytes and this hematopoietic niche have not been investigated. Here, we identify late erythroblasts as a new host cell for P falciparum sexual stages and show that gametocytes can fully develop inside these nucleated cells in vitro and in vivo, leading to infectious mature gametocytes within reticulocytes. Strikingly, we found that infection of erythroblasts by gametocytes and parasite-derived extracellular vesicles delay erythroid differentiation, thereby allowing gametocyte maturation to coincide with the release of their host cell from the bone marrow. Taken together, our findings highlight new mechanisms that are pivotal for the maintenance of immature gametocytes in the bone marrow and provide further insights on how Plasmodium parasites interfere with erythropoiesis and contribute to anemia in malaria patients.

Allogeneic dendritic cells stimulated with antibodies against HLA class II polarize naive T cells in a follicular helper phenotype.

Follicular helper T cells (Tfh) are crucial for the production of high-affinity antibodies, such as alloantibodies, by providing the signals for B-cell proliferation and differentiation. Here, we demonstrate that human allogeneic dendritic cells (DC) stimulated with antibodies against HLA class II antigens preferentially differentiate human naive CD4+ T cells into Tfh cells. Following coculture with DCs treated with these antibodies, CD4+ T cells expressed CXCR5, ICOS, IL-21, Bcl-6 and phosphorylated STAT3. Blockade of IL-21 abrogated Bcl-6, while addition of the IL-12p40 subunit to the coculture increased CXCR5, Bcl-6, phosphorylated STAT3 and ICOS, indicating that they were both involved in Tfh polarization. We further phenotyped the peripheral T cells in a cohort of 55 kidney transplant recipients. Patients with anti-HLA-II donor-specific antibodies (DSA) presented higher blood counts of circulating Tfh cells than those with anti-HLA-I DSAs. Moreover, there was a predominance of lymphoid aggregates containing Tfh cells in biopsies from patients with antibody-mediated rejection and anti-HLA-II DSAs. Collectively, these data suggest that alloantibodies against HLA class II specifically promote the differentiation of naive T cells to Tfh cells following contact with DCs, a process that might appear in situ in human allografts and constitutes a therapeutic target.

Impaired Secretion of TNF-α by Monocytes Stimulated With EBV Peptides Associates With Infectious Complications After Kidney Transplantation.

BACKGROUND: The successful development of immunosuppressive agents has paradoxically led to an era in which adverse effects of immunosuppression, such as infections and cancer, are now a major concern in solid organ recipients. Nevertheless, the main focus of immune monitoring research remains the identification of rejection. There is currently no clinical tool to assess the net state of immunosuppression or to identify patients at increased risk of infectious complications. METHODS: We report a prospective, longitudinal study in which we conducted detailed phenotyping of over 300 peripheral blood mononuclear cell samples from 45 kidney recipients during the first 24 months posttransplant. Patients were classified as cases or controls according to the following events: an opportunistic infection, recurring bacterial infections, or de novo neoplasia. RESULTS: Using a training cohort, an exploratory analysis revealed that the TNFα response to synthetic Epstein-Barr virus peptides by CD14CD16 monocytes was lower in cases. A classifier rule based on 2 or greater consecutive values below a threshold of 73% of TNFα-positive cells provided a sensitivity and specificity of 83%. In the validation cohort, the assay exhibited a sensitivity of 90% and a specificity of 63%. Analysis of IFNγ responses by T cells showed no correlation with the cases' phenotype. The association between overimmunosuppression status and the monocyte response was independent of age, renal function, and immunosuppressive regimen. CONCLUSIONS: These data suggest that patients with infectious complications posttransplantation have lower CD14CD16 monocyte responses to Epstein-Barr virus peptides. This assay seems promising to help personalize the immunotherapy.

IL-6 production by monocytes is associated with graft function decline in patients with borderline changes suspicious for acute T-cell-mediated rejection: a pilot study.

Although borderline changes (BL) suspicious for acute T-cell-mediated rejection represent a diagnostic category, its clinical relevance is questioned leading to heterogeneous therapeutic management. We hypothesized that measuring IL-6 secretion by peripheral blood mononuclear cells identifies patients with ongoing graft damage. We examined the association between secreted IL-6 and the change in estimated glomerular filtration rate at 6 months after the biopsy (ΔeGFR). We then conducted phenotypic and functional studies on patient and mouse innate immune cells in the blood and the kidney. In a training set, ΔeGFR was strongly associated with IL-6 levels, showing a clinically meaningful decline of 4.6 ± 1.5 ml/min per increase in log10 IL-6 (P = 0.001). These results were consistent after adjustment and were reproduced in a validation cohort. Phenotyping of peripheral blood cells revealed that the main source of IL-6 was CD14+ CD16- CCR2+ HLA-DR+ CD86+ CD11c+ inflammatory monocytes. There was a significant correlation between IL-6 secretion and interstitial dendritic cell density in the biopsy. Finally, characterization of mouse kidney dendritic cells revealed that they share features with macrophages and function as effector cells secreting IL-6. In conclusion, measuring IL-6 secreted by peripheral blood cells can be useful in the management of patients with BL in the absence of a concurrent inflammatory condition.

Clinical relevance of circulating antibodies and B lymphocyte markers in allograft rejection.

The main challenge in solid organ transplantation remains to tackle antibody-mediated rejection. Our understanding of the antibody-mediated response and the capacity to detect it has improved in the last decade. However, the sensitivity and specificity of the current clinical tools to monitor B cell activation are perfectible. New strategies, including the refinement in the characterization of HLA and non-HLA antibodies, as well as a better understanding of the circulating B cell phenotype will hopefully help to non-invasively identify patients at risk or undergoing antibody-mediated allograft damage. The current review discusses the current knowledge of the B cell biomarkers in solid organ transplantation, with a focus on circulating antibodies and peripheral B cells.

Innate immunity in solid organ transplantation: an update and therapeutic opportunities.

Innate immunity is increasingly recognized as a major player in transplantation. In addition to its role in inflammation in the early post-transplant period, innate immunity shapes the differentiation of cells of adaptive immunity, with a capacity to promote either rejection or tolerance. Emerging data indicate that innate allorecognition, a characteristic previously limited to lymphocytes, is involved in allograft rejection. This review briefly summarizes the physiology of each component of the innate immune system in the context of transplantation and presents the current or promising therapeutic applications, such as cellular, anticomplement and anticytokine therapies.