Hyaluronan (HA) is a prominent component of the extracellular matrix at many sites of chronic inflammation, including type 1 diabetes (T1D), multiple sclerosis, and numerous malignancies. Recent publications have demonstrated that when HA synthesis is inhibited using 4-methylumbelliferone (4-MU), beneficial effects are observed in several animal models of these diseases. Notably, 4-MU is an already approved drug in Europe and Asia called “hymecromone” where it is used to treat biliary spasm. However, there is uncertainty regarding how 4-MU treatment provides benefit in these animal models and the potential long-term consequences of HA inhibition. Here, we review what is known about how HA contributes to immune dysregulation and tumor progression. Then, we review what is known about 4-MU and hymecromone in terms of mechanism of action, pharmacokinetics, and safety. Finally, we review recent studies detailing the use of 4-MU to treat animal models of cancer and autoimmunity.

Rapamycin/interleukin-2 (IL-2) combination treatment of NOD mice effectively treats autoimmune diabetes. We performed a phase 1 clinical trial to test the safety and immunologic effects of rapamycin/IL-2 combination therapy in type 1 diabetic (T1D) patients. Nine T1D subjects were treated with 2–4 mg/day rapamycin orally for 3 months and 4.5 × 10 6 IU IL-2 s.c. three times per week for 1 month. β-Cell function was monitored by measuring C-peptide. Immunologic changes were monitored using flow cytometry and serum analyses. Regulatory T cells (Tregs) increased within the first month of therapy, yet clinical and metabolic data demonstrated a transient worsening in all subjects. The increase in Tregs was transient, paralleling IL-2 treatment, whereas the response of Tregs to IL-2, as measured by STAT5 phosphorylation, increased and persisted after treatment. No differences were observed in effector T-cell subset frequencies, but an increase in natural killer cells and eosinophils occurred with IL-2 therapy. Rapamycin/IL-2 therapy, as given in this phase 1 study, resulted in transient β-cell dysfunction despite an increase in Tregs. Such results highlight the difficulties in translating therapies to the clinic and emphasize the importance of broadly interrogating the immune system to evaluate the effects of therapy.

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Data generated by the numerous clinical trials conducted annually worldwide have the potential to be extremely beneficial to the scientific and patient communities. This potential is well recognized and efforts are being made to encourage the release of raw patient-level data from these trials to the public. The issue of sharing clinical trial data has recently gained attention, with many agreeing that this type of data should be made available for research in a timely manner. The availability of clinical trial data is most important for study reproducibility, meta-analyses, and improvement of study design. There is much discussion in the community over key data sharing issues, including the risks this practice holds. However, one aspect that remains to be adequately addressed is that of the accessibility, quality, and usability of the data being shared. Herein, experiences with the two current major platforms used to store and disseminate clinical trial data are described, discussing the issues encountered and suggesting possible solutions.