In this report we describe a patient who, after allogeneic bone marrow transplantation from her HLA-identical sister, developed polyendocrine failure in the form of Type 1 (insulin-dependent) diabetes mellitus and hypothyroidism. This was the result of the transfer of donor lymphoid cells which were activated by allogeneic bone marrow transplantation. The full chimerism of the recipient was demonstrated by restriction fragment length polymorphism analysis from nucleated blood cells and fibroblast DNA. During the 9-year follow-up, the donor developed hypothyroidism and signs of pre-Type 1 diabetes. This clinical observation resembles the adoptive transfer of diabetes observed in non-obese-diabetic mice and BB rats and confirms the role of immune processes in the pathogenesis of this disease.

In order to gain insight into the interaction between autoimmunity and viral infection in the onset of insulin-dependent diabetes, non-obese diabetic (NOD) mice which spontaneously develop autoimmune diabetes were inoculated with the diabetogenic variant of the encephalomyocarditis virus (EMCV-D) before the onset of the disease. The pre-diabetic period was divided into two phases: the early phase (days 88 to 116) during which development of spontaneous diabetes is rare and the late phase (day 123 to 200) during which the incidence of spontaneous diabetes is high. As controls ICR mice of common ancestry were also inoculated. During the early phase diabetes was observed in 4/10 inoculated, 0/13 control NOD and 7/13 inoculated ICR males vs. 6/12 inoculated, 1/11 control NOD and 0/15 inoculated ICR females. However, in NOD female, virus-induced diabetes prevalence was variable from one experiment to another. In parallel the flow cytometric analysis showed a high percentage of L3T4+ T lymphocytes in the pancreas of inoculated female NOD mice 10 days after the infection. At this time a large proportion of both L3T4+ and Ly-2+ cells expressed the interleukin 2 receptor. During the late phase no new case of diabetes occurred in inoculated NOD mice but one case was observed in control NOD males and five in control NOD females. This prevention of autoimmune diabetes was constantly found in other experiments. Insulitis was milder in inoculated NOD mice of both sexes than in control NOD. Adoptive transfer of diabetes into irradiated 8-week-old males by splenocytes from 28-week-old females was successful in five out seven attempts with control splenocytes and in zero out of six attempts with splenocytes from inoculated mice. This immunosuppression was specific as the ability of lymphocytes to respond to soluble or allogeneic antigens was preserved. In the early phase EMCV-D precipitated the onset of diabetes in females NOD mice by amplifying L3T4+ T lymphocyte-mediated immune mechanisms. During the late phase viral infection had lessened immune processes in animals which had resisted or recovered from virus-induced diabetes.

Glutamic acid decarboxylase autoantibodies (GAD-A) and tyrosine phosphatase IA-2 autoantibodies (IA2-A) were measured in sera of 50 recently diagnosed (<6 wk, 33% younger than 15 yr), 19 short-term (1 to 9 yr, 35% with onset age below 15 yr) and 89 long-standing diabetic patients (>10 yr, 57% with onset age below 15 yr). Complications were assessed by clinical examination, retinal angiographs and microalbuminuria measurement. Both prevalences and levels of GAD-A and IA2-A decreased with increasing duration of diabetes. However even in those with long duration diabetes, 15 to 63% of the sera were still positive for one or two antibodies. In the group with onset after the age of 15 yr, significantly higher prevalences and levels of GAD-A (but not IA2-A) was observed in comparison with the group with earlier onset. No association was found with any microvascular complications in any group. We conclude that GAD-A and IA2-A persist in some diabetic patients, despite a long duration. Persistence of GAD-A was greatest in those with postpubertal disease onset. We speculate that persistence of some beta-cells or specific environmental factors can sustain one autoimmune reaction especially in some postpubertal-onset diabetic patients.

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Background: Single-injection viscosupplementation is currently performed with cross-linked hyaluronan (e.g., Durolane®) for treating symptomatic knee osteoarthritis. Objective: This first-in-human study evaluated the safety and performance of single-injection treatment with non-crosslinked KiOmedine®CM-Chitosan. Methods: Patients with painful knee osteoarthritis were randomly assigned to the KiOmedine®CM-Chitosan (n=63) or Durolane® (n=32) group. Patients were blinded to treatment and followed up for 26 weeks. Durolane® was used as scientific control to ensure the validity of the study and reliability of results. No direct comparison was performed between the two groups. The primary objective was defined as an intra-group effect size of 0.8 at 13 weeks post-injection compared to baseline on WOMAC-A (pain). Secondary outcomes included self-reported knee stiffness and knee function, responder rate, quality-of-life questionnaires, and safety. Results: The primary objective for both the KiOmedine®CM-Chitosan and the Durolane® groups was met: mean pain reduction of 62.5% (effect size 2.08) for the KiOmedine®CM-Chitosan group and 62.4% (effect size 2.28) for the Durolane® group. Secondary performance outcomes showed all clinically relevant treatment effects over 26 weeks for both groups (p<0.05). Treatment-related adverse events were more often reported in the KiOmedine®CM-Chitosan than Durolane® group and were limited to local reactions. No serious treatment-related adverse events were reported. Conclusion: A single intra-articular injection of non-crosslinked KiOmedine®CM-Chitosan is safe and effective for treating symptomatic knee osteoarthritis with a high responder rate. Pain reduction is maintained for 6 months with a high responder rate. The clinical trial registration number: NCT03679208.