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Objective To identify early factors associated with disease course in patients with juvenile idiopathic inflammatory myopathies (IIMs). Methods Univariable and multivariable multinomial logistic regression analyses were performed in a large juvenile IIM registry (n = 365) and included demographic characteristics, early clinical features, serum muscle enzyme levels, myositis autoantibodies, environmental exposures, and immunogenetic polymorphisms. Results Multivariable associations with chronic or polycyclic courses compared to a monocyclic course included myositis-specific autoantibodies (multinomial odds ratio [OR] 4.2 and 2.8, respectively), myositis-associated autoantibodies (multinomial OR 4.8 and 3.5), and a documented infection within 6 months of illness onset (multinomial OR 2.5 and 4.7). A higher overall clinical symptom score at diagnosis was associated with chronic or monocyclic courses compared to a polycyclic course. Furthermore, severe illness onset was associated with a chronic course compared to monocyclic or polycyclic courses (multinomial OR 2.1 and 2.6, respectively), while anti-p155/140 autoantibodies were associated with chronic or polycyclic courses compared to a monocyclic course (multinomial OR 3.9 and 2.3, respectively). Additional univariable associations of a chronic course compared to a monocyclic course included photosensitivity, V-sign or shawl sign rashes, and cuticular overgrowth (OR 2.2-3.2). The mean ultraviolet index and highest ultraviolet index in the month before diagnosis were associated with a chronic course compared to a polycyclic course in boys (OR 1.5 and 1.3), while residing in the Northwest was less frequently associated with a chronic course (OR 0.2). Conclusion Our findings indicate that myositis autoantibodies, in particular anti-p155/140, and a number of early clinical features and environmental exposures are associated with a chronic course in patients with juvenile IIM. These findings suggest that early factors, which are associated with poorer outcomes in juvenile IIM, can be identified.

INTRODUCTION: Haploidentical allogeneic stem cell transplantation (haplo-SCT) incurs a risk of bidirectional immune reactions with either severe acute graft versus host disease (aGVHD) or graft rejection. Induction of immune tolerance with post-graft cyclophosphamide dramatically improves the outcomes of haplo-SCT. However the optimal duration and the combination of systemic immunosuppressive agents in haplo-SCT remain controversial. Ultra-low dose interleukin 2 (ULD IL-2) preferentially expands regulatory T cells (Tregs) and natural killer (NK) cells, promoting both GVHD prevention and graft versus leukemia (GVL) effects. These properties suggest that ULD IL-2 could play a useful role in haplo-SCT. Here we report the outcomes of a pilot study to determine the safety and feasibility of ULD IL-2 as GVHD prophylaxis in haploidentical allo-SCT (14-H-0180, Clinical Trials.gov ID: NCT02226861) METHODS: Ten subjects with high risk hematological malignancies received a myeloablative conditioning regimens of fludarabine 120mg/m2 (day -10 to day -8) and total body irradiation (TBI; 600-1200 cGy, day -10 to day -6). Thereafter the subjects received donor lymphocyte infusion (DLI) products (2x108 CD3+/kg) on day -6, followed by post-DLI cyclophosphamide 120mg/kg on days -3 and -2. CD 34+ selected, peripheral blood stem cell product was infused on day 0. Sirolimus was initiated on day -1 with goal trough level of 5-12ng/mL until day+60. ULD-IL2 (aldesleukin, 100,000 IU/m2) was given subcutaneously daily for 12 weeks starting day +1. Peripheral blood mononuclear cells (PBMC) and plasma samples were collected at days 14, 28, 60, 84, 100 post-transplant. Multi-color flow cytometry immunophenotyping assay were performed to characterize the subsets of memory T cells, Tregs, NK cells, and monocytes with various functional markers. Plasma levels of biomarkers (ST2, Reg3α, sTNFR1, ANG1, IL-6) were measured using a multiplex microfluidic channel assay. RESULTS: The median age at transplant was 35 years (range 20-66). Most subjects had a high risk EBMT score (median 4, range 2-7) and HCT co-morbidity index (median 4, range 2-7). All subjects achieved successful engraftment (neutrophil >500/uL; median 13 days, platelet >20k/uL; median 15 days) and rapid full donor myeloid and lymphoid chimerism by day 21. At median follow up of 6 month, the overall survival was 71%. One subject died of hepatic veno-occulusive disease (VOD) on day 32 and one subject died of relapse on day 178. All evaluable subjects tolerated ULD-IL2 without significant toxicities. Four subjects experienced either de-novo or rapid exacerbation of acute GVHD after discontinuation of ULD IL-2, resulting in the cumulative incidence of grade II-IV aGVHD of 61% and grade III-IV aGVHD of 36% (Figure A). ULD IL-2 expanded and maintained Helios+FoxP3+Tregs population (pre-transplant, 4.7%±3.1%; day 30, 36.2%±23.1%; day 84, 17.4%±10.6%) as well as CD56brightNK cells population (pre-transplant, 10.7%±13.7%; day 30, 49.7%±10.8%; day 84, 26.1%±6.8%). However on discontinuation of ULD IL-2 both populations decreased to low levels within one week. The timing of aGVHD correlated with a fall of %Tregs in PBMC and a sharp increase of ST2 level in plasma (Figure B). CONCLUSION: ULD IL-2 can be safely administered as GVHD prophylaxis after haplo-SCT. Rebound GVHD after discontinuation of ULD IL-2 implies that donor-derived Tregs acquired dependency to exogenous ULD IL-2. Our study is proof of principle that ULD IL-2 induces immune tolerance through Tregs expansion in haplo-SCT, inspiring further clinical and basic researches in human IL-2 biology. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

Human leucocyte antigen (HLA) antibodies have been implicated in transfusion-related acute lung injury, but the probability that the transfusion of a blood component containing HLA antibodies will cause a reaction is not known. This study compared the prevalence of reactions associated with the transfusion of platelet components with and without HLA antibodies.This retrospective study tested 96 consecutive apheresis platelet donors for HLA class I and II antibodies. Matched control donors without HLA antibodies were selected and records were reviewed to determine the proportion of components from each group that caused reactions. In addition, all apheresis platelet donors involved with two or more reactions were identified and tested for HLA class I antibodies.Five of the 96 donors had antibodies to class I or class II antigens and, of these, four had components transfused. The prevalence of reactions to components from these four donors with HLA antibodies and the 12 matched control donors without antibodies was similar (three reactions to 167 transfusions or 1.8% vs. three to 295 or 1.0%, respectively, P = 0.32). A retrospective review of the transfusion records from all platelet donors found that components from 22 caused two or more reactions and three (13.6%) had antibodies to HLA class I compared to 4.2% of the consecutively selected donors (P = 0.12). None of the patients experienced transfusion-related acute lung injury.Reactions associated with transfusion of apheresis platelets containing HLA antibodies are unusual.

HLA-A2-restricted CTL responses to immunodominant HIV-1 epitopes do not appear to be very effective in the control of viral replication in vivo. In this study, we studied human CD8+ T cell responses to the subdominant HLA-A2-restricted epitope TV9 (Gag p24(19-27), TLNAWVKVV) to explore the possibility of increasing its immune recognition. We confirmed in a cohort of 313 patients, infected by clade B or clade C viruses, that TV9 is rarely recognized. Of interest, the functional sensitivity of the TV9 response can be relatively high. The potential T cell repertoires for TV9 and the characteristics of constituent clonotypes were assessed by ex vivo priming of circulating CD8+ T cells from healthy seronegative donors. TV9-specific CTLs capable of suppressing viral replication in vitro were readily generated, suggesting that the cognate T cell repertoire is not limiting. However, these cultures contained multiple discrete populations with a range of binding avidities for the TV9 tetramer and correspondingly distinct functional dependencies on the CD8 coreceptor. The lack of dominant clonotypes was not affected by the stage of maturation of the priming dendritic cells. Cultures primed by dendritic cells transduced to present endogenous TV9 were also incapable of clonal maturation. Thus, a diffuse TCR repertoire appeared to be an intrinsic characteristic of TV9-specific responses. These data indicate that subdominance is not a function of poor immunogenicity, cognate TCR repertoire availability, or the potential avidity properties thereof, but rather suggest that useful responses to this epitope are suppressed by competing CD8+ T cell populations during HIV-1 infection.

Bibliography: p. 114-116, Medea, a 'Creative Work' adapted from Euripides' script, was produced by the Department of Drama at the University of Calgary, in the University Theatre from February 24 - March 6, 2004. This thesis documents the process of creation leading to the adaptation and the production. The following is an exploratory document, written to question, rather than provide answers to, the creative process. It is a document that dwells on things mysterious -things squirming beneath our limited ability to 'know'. My hope is that you, the reader, will journey with me - into the 'mad' and 'murky' depths of the psychological unknown.