IntroductionDisease activity and therapy show an impact on cellular and serological parameters in patients with systemic lupus erythematosus (SLE). This study was performed to compare the influence of mycophenolate mofetil (MMF) and cyclophosphamide (CYC) therapy on these parameters in patients with flaring, organ-threatening disease.MethodsSLE patients currently receiving CYC (n = 20), MMF (n = 25) or no immunosuppressive drugs (n = 22) were compared using a cross-sectional design. Median disease activity and daily corticosteroid dose were similar in these treatment groups. Concurrent medication, organ manifestations, and disease activity were recorded, and cellular and serological parameters were determined by routine diagnostic tests or flow cytometric analysis. In addition follow-up data were obtained from different sets of patients (CYC n = 24; MMF n = 23).ResultsAlthough both drugs showed a significant effect on disease activity and circulating B cell subsets, only MMF reduced circulating plasmablasts and plasma cells as well as circulating free light chains within three months of induction therapy. Neither MMF nor CYC were able to reduce circulating memory B cells. MMF lowered IgA levels more markedly than CYC. We did not observe a significant difference in the reduction of IgG levels or anti-dsDNA antibodies comparing patients receiving MMF or CYC. In contrast to MMF, induction therapy with CYC was associated with a significant increase of circulating CD8+ effector T cells and plasmacytoid dendritic cells (PDCs) after three months.ConclusionsThe results indicate differences between MMF and CYC with regard to the mechanism of action. MMF, but not CYC, treatment leads to a fast and enduring reduction of surrogate markers of B cell activation, such as circulating plasmablasts, plasma cells and free light chains but a comparable rate of hypogammaglobulinemia.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0603-8) contains supplementary material, which is available to authorized users.

Background. Prophylactic ganciclovir (GCV) is used in high-risk renal transplant patients to prevent acute cytomegalovirus (CMV) disease, but its impact on inflammation within the allograft itself remains undefined. Methods. To study the effect of GCV prophylaxis on allograft inflammation, murine CMV (MCMV)-infected allo-grafts were analyzed in a murine donor positive/recipient negative allogeneic renal transplantation model by flow cytometry and immunofluorescent staining. Results. By flow cytometry, CD45+ leukocyte infiltrates were more abundant in MCMV-infected allografts at 14 days posttransplant compared with uninfected grafts (P<0.01) and decreased in the presence of GCV (P<0.05). CD11c+ dendritic cells, Gr-1+ myeloid cells, CD204+ macrophages, and CD49b+ natural killer cells were reduced in GCV-treated allografts compared with MCMV-infected grafts without GCV treatment (P<0.05). However, GCV failed to reduce these cell types to levels found in MCMV-uninfected allografts. By day 7 after cessation of GCV prophylaxis, dendritic cells, macrophages, and natural killer cells increased in number and became statistically indistinguishable from numbers of cells found in MCMV-infected allografts without GCV. GCV treatment did not affect the numbers of CD4+, CD8+, or CD19+/B220+ lymphocytes infiltrating the allografts. Infiltrates were confirmed histologically by immunofluorescent staining for CD3+ and CD11b+ cells. Conclusions. In this model, MCMV-infected allografts developed significantly greater innate and adaptive leukocytic infiltrates compared with uninfected grafts. GCV attenuated the MCMV-associated innate leukocyte infiltrates in infected allo-grafts but not the lymphocytic infiltrates. The attenuated innate response was limited to the period of GCV prophylaxis.

Malignant gliomas are the most common primary brain tumor and are characterized by rapid and highly invasive growth. Because of their poor prognosis, new therapeutic strategies are needed. Oncolytic virotherapy (OV) is a promising strategy for treating cancer that incorporates both direct viral replication mediated and immune mediated mechanisms to kill tumor cells. C134 is a next generation Δγ134.5 oHSV-1 with improved intratumoral viral replication. It remains safe in the CNS environment by inducing early IFN signaling which restricts its replication in non-malignant cells. We sought to identify how C134 performed in an immunocompetent tumor model that restricts its replication advantage over first generation viruses. To achieve this we identified tumors that have intact IFN signaling responses that restrict C134 and first generation virus replication similarly. Our results show that both viruses elicit a T cell mediated anti-tumor effect and improved animal survival but that subtle difference exist between the viruses effect on median survival despite equivalent in vivo viral replication. To further investigate this we examined the anti-tumor activity in immunodeficient mice and in syngeneic models with re-challenge. These studies show that the T cell response is integral to C134 replication independent anti-tumor response and that OV therapy elicits a durable and circulating anti-tumor memory. The studies also show that repeated intratumoral administration can extend both OV anti-tumor effects and induce durable anti-tumor memory that is superior to tumor antigen exposure alone.

BACKGROUND Human cytomegalovirus (CMV) infection is associated with inferior survival in renal transplant patients, and ganciclovir (GCV) prophylaxis is associated with improved survival. In a murine CMV (MCMV) renal transplant model, GCV prophylaxis improved innate infiltrates and allograft damage during the period of prophylaxis. In this study, late effects were examined after discontinuation of prophylaxis. METHODS MCMV D+/R− and D−/R− allogeneic transplants were performed with cyclosporine immunosuppression. One D+/R− cohort received GCV prophylaxis for 14 days post-transplant, followed by 28 days without GCV. At 42 days post-transplant, grafts were analyzed for histologic tissue damage and immune infiltrates. Another D+/R− cohort was treated with anti-NK1.1 antibodies for 14 days post-transplant and compared to animals without NK depletion. RESULTS At day 42, MCMV infected transplants had higher damage scores (15.6+/−0.6) compared to uninfected transplants (8.3+/−0.9) (p<0.01), which improved in GCV treated allografts (9.5+/−1.4). MCMV infected grafts contained greater frequencies of natural killer (NK) cell and myeloid infiltrates compared to uninfected grafts (p<0.05), which decreased in the GCV treated grafts. NK depletion improved allograft histology of MCMV infected grafts. CONCLUSIONS MCMV infection exacerbates late renal allograft damage and is associated with NK and myeloid cell infiltrates. GCV prophylaxis reduces allograft injury, NK cell and myeloid infiltrates even after cessation of prophylaxis. NK depletion in MCMV infected transplants also improves histology. These results suggest that GCV prophylaxis may have a long-term beneficial effect upon CMV infected renal allografts, and suggest a potential role for NK cells in the pathogenesis of CMV associated allograft injury.

The transmembrane receptor Notch1 plays a crucial role in differentiation and apoptosis of hematopoietic cells. To investigate the influence of Notch1 on apoptosis and cell growth of mature murine B cells, we transduced the murine B-lymphoma line NYC 31