Expression of transcription factor Fli-1 is implicated in the development of glomerulonephritis. Fli-1 heterozygous knockout (Fli1+/−) NZM2410 mice, a murine model of lupus, had significantly improved survival and reduced glomerulonephritis. In this study, we found that infiltrated inflammatory cells were significantly decreased in the kidneys from Fli-1+/− NZM2410 mice. The expression of Monocyte chemoattractant protein-1 (MCP-1) was significantly decreased in kidneys from Fli-1+/− NZM2410 mice. The primary endothelial cells isolated from the kidneys of Fli-1+/− NZM2410 mice produced significantly less MCP-1. In endothelial cells transfected with specific Fli-1 siRNA the production of MCP-1 was significantly reduced compared to cells transfected with negative control siRNA. By Chromatin Immunoprecipitation (ChIP) assay, we further demonstrated that Fli-1 directly binds to the promoter of the MCP-1 gene. Our data indicate that Fli-1 impacts glomerulonephritis development by regulating expression of inflammatory chemokine MCP-1 and inflammatory cell infiltration in the kidneys in the NZM2410 mice.

replete HLA-mismatched haploidentical transplantation (HIDT) with post-transplant cyclophosphamide is increasingly becoming an acceptable treatment approach for patients lacking timely access to a suitably matched related donor transplant (MRDT) or matched unrelated donor transplant (MUDT). Multiple recent registry and single-center studies have shown comparable overall survival (OS) and disease-free survival (DFS) rates among HIDT, MRDT, and MUDT with a significantly lower risk of acute and chronic graft-versus-host disease (GVHD) among HIDT recipients. Candidates for allogeneic hematopoietic stem cell transplantation (HSCT) often have access to multiple donor sources, and a relevant question is whether outcomes can be improved with a younger HLA-mismatched haploidentical donor (35 years) rather than an older matched related donor (35 years) or matched unrelated donor (35 years). We analyzed 406 consecutive allogenic HSCT recipients, with a median age of 54 years (range, 19 to 77), after a MRDT with a donor age of 35 years (n = 222), MUDT with a donor age of 35 years (n = 91), and HIDT with a donor age of 35 years (n = 93). Median follow-up time for survivors was 51.5 months. Compared with MRDT and MUDT, HIDT recipients had a similar median age at time of HSCT, hematopoietic cell transplant comorbidity index, disease risk index distribution, and donor recipient sex matching. The survival estimates and relapse incidence at 3 years post-HSCT were OS (64% for MRDT, 54% for MUDT, and 62% for HIDT), DFS (55% for MRDT, 44% for MUDT, and 58% for HIDT), Transplant related mortality (TRM) (19% for MRDT, 16% for MUDT, and 18% for HIDT), and relapse (26% for MRDT, 37% for MUDT, and 24% for HIDT). HIDT recipients had better 3-year relapse rates compared with MUDT recipients (24% versus 37%, P= .048), with similar DFS and OS in a univariate analysis. MRDT recipients had a better relapse rate (26% versus 37%, P = .042) compared with MUDT recipients. Recipients of HIDT also had significantly lower rates of moderate to severe chronic GVHD compared with MRDT and MUDT recipients (P = .01). Multivariable analysis showed no effect of donor on OS, DFS, relapse, and TRM. Recipients of HIDT from a young donor 35 years had similar OS, lower rates of chronic GVHD, and better chronic GVHD-free, relapse-free survival compared with patients undergoing transplantation with an MRD or a MUD donor 35 years. This study suggests that given a situation where a choice between a young haploidentical relative and an older matched unrelated donor is to be made, one can achieve similar survival with a haploidentical donor and significantly lower rates of chronic GVHD.

SUMMARYDogs can develop systemic lupus erythematosus syndromes that are clinically similar to those seen in humans. In contrast, previous observations suggest differences in their autoatitibody reactivity patterns against histones and DNA which are components of the nucleosome in chromatin. The objective of this study was to assess comprehensively the levels of autoantibodies against histone, DNA and nucleosome antigens in a population of lupus dogs. The specificities of antibodies in lupus and control dog sera were determined using IgM-and IgG-specific reagents in an ELISA against a variety of chromatin antigens. When compared with control sera, IgG antibodies to individual histones HI, H2A, H3 and H4 were significantly higher in the lupus group. In contrast, we did not detect IgG antibodies specific for H2B, H2A-H2B, DNA, H2A-H2B-DNA or nucleosomes in lupus dogs. There was no significant increase in any of the IgM specificities tested. Therefore, the reactivity pattern to nucleosome antigens in canine lupus is restricted to IgG antibodies against individual histones HI, H2A, H3 and H4. This stands In contrast with human and murine lupus, where autoantibodies are directed against a wide variety of nucleosomal determinants, suggesting that unique mechanisms lead to the expansion of anti-histone antibody clones in canine lupus. The high incidence of glomerulonephritis in dog lupus suggests that anti-DNA antibodies are not required for the development of this complication, whereas IgG antihistone antibodies may be relevant to its pathogenesis.

Introduction: Cytomegalovirus (CMV) is a leading cause of morbidity following allogenenic hematopoietic stem cell transplant (HSCT). Letermovir (LTV), an orally available antiviral drug which inhibits the CMV-terminase complex, was recently approved for CMV prophylaxis in CMV-seropositive HSCT recipients due to its ability to significantly reduce the risk of clinically significant CMV infection and its favorable toxicity profile. In the pivotal phase 3 study, subgroup analysis suggested increased benefit of LTV in patients at higher risk for CMV infection (i.e. unrelated or haploidentical donor (HID) vs. matched related donor), however HID transplants represented only 16% of the study population1. Therefore, we conducted a retrospective analysis of CMV reactivation rates, before and after the initiation of routine LTV prophylaxis, to determine the real-world safety and efficacy of LTV in an unselected group of CMV-seropositive high risk HSCT recipients, including a large number of HID transplants. Methods: We conducted a retrospective review of 106 consecutive CMV-seropositive high risk allogeneic HSCT recipients between 2017 and 2019. We compared the incidence of CMV infection immediately prior to the initiation of routine LTV prophylaxis in high risk transplant recipients (pre-LTV) (n=41) to that occurring after the initiation of LTV prophylaxis (post-LTV) (n=63). HSCT recipients were considered high risk if they had received at least one of the following: transplant from a haploidentical donor, matched unrelated donor, umbilical cord blood donor source or received anti-thymocyte globulin. CMV infection was defined as the need for pre-emptive therapy or documented CMV disease. The cumulative incidence (CI) of CMV infection at 100 days and 180 days were calculated to accommodate death as a competing risk. We used the Wald test to compare the CI at 100 and 180 days between the two cohorts. Results: Baseline characteristics of the pre- and post-LTV cohorts were similar, with HID transplants making up the majority of HSCTs in both groups, 65% and 64% respectively. We found a significantly lower CI of CMV infection at both 100 and 180 days in the post-LTV cohort when compared to the pre-LTV cohort (19.4% vs. 68.3% and 27.6% vs. 71% respectively; p<0.001) (Fig. 1). Despite lower CMV incidence following LTV prophylaxis, there was no significant difference in median time to CMV infection when compared to patients not receiving LTV prophylaxis (median [range] 40 [10, 243] vs. 36 [10, 180] days, p=0.72). The CI of CMV disease was 1.6% in the post-LTV cohort vs. 7.3% in the pre-LTV cohort (p=0.186). No significant differences were observed in any other outcome variable including overall survival, non-relapse mortality, relapse, acute graft-versus-host disease (GVHD) or time to neutrophil or platelet recovery. A preplanned subset analysis limited to HID transplant recipients (Fig. 2) again demonstrated a significant decrease in CMV infection in the post-LTV cohort at 100 and 180 days (27.9% vs. 80.8% and 34.6% vs. 84.6% respectively; p<0.001). Conclusion: This single center analysis confirms the benefit of LTV prophylaxis in reducing the risk of clinically significant CMV infection in unselected high risk CMV-seropositive HSCT patients, including a substantial number of HID transplant recipients. We found no significant impact of LTV prophylaxis on any other transplant outcome including hematologic engraftment, GVHD, relapse or mortality. In contrast to the pivotal phase 3 study, we saw few CMV infections occurring past day 100 after discontinuation of LTV prophylaxis. Future planned analyses will include comparisons of antiviral usage and associated toxicities (i.e. cytopenias), overall treatment charges and hospitalization/resource utilization. Disclosures LaPorte: Merck: Speakers Bureau.

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