Fathman Lab In the Division of Immunology & Rheumatology

Current Lab Projects

Risk and Progression of T1D

Under funding from JDRF, we have been collaborating with TrialNet, a network of researchers and sample repositories studying type 1 diabetes (T1D). We are working to identify biomarkers in whole blood that can predict the risk and rate of progression of type 1 diabetes.

Currently, the best way to predict an individual’s risk of developing T1D is by measuring autoantibodies to pancreatic antigens. Currently, 85% of patients who develop T1D do not have a family history of the disease, and only 15% of individuals who present with one autoantibody progress to hyperglycemia within 10 years. By identifying biomarkers in whole blood of diabetes-related cohorts compared with healthy controls, we hope to improve early detection of at-risk individuals. Our lab uses microarrays, RNAseq, qPCR, and NanoString arrays to investigate first-degree relatives of people with diabetes, non-diabetic autoantibody-positive individuals, and frankly diabetic patients.


Low-dose IL-2 Therapy for Treatment of Autoimmune Diseases

We are working on a hypothesis that the major adaptive immune defect in autoimmunity and allergy is a druggable target in immune regulation, the regulatory T cell (Treg) IL-2 receptor (IL-2R).

The use of low dose IL-2 to target regulatory Tregs that constitutively express the high affinity receptor IL-2R has recently generated interest as a potential therapeutic for autoimmune and allergic diseases. The current paradigm supporting this is that the high affinity of the IL-2R on Tregs is the key to the therapeutic effect.

However, recent studies in our lab have demonstrated that it is not simply affinity of the Treg IL-2R, but the downstream signaling pathway following receptor engagement that distinguishes Treg IL-2R activation from that of conventional CD4 T cells. Unpublished studies demonstrate that the ubiquitin E3 ligase GRAIL, constitutively expressed in human and mouse Tregs, delays IL-2R desensitization by inhibiting the posttranslational modification (neddylation) of the cullin5 component of the SOCS3 cullin ring ligase that normally degrades IL-2Rβ chain associated pJAK1 to desensitize IL-2R to stop the signaling cascade.

This observation has lead to a novel hypothesis: by specifically blocking IL-2Rβ chain associated pJAK1/SOCS3 engagement in Tregs, we can delay IL-2R desensitization and support increased pStat5 transcription to “turn on” the Tregs to treat inflammatory diseases.

To test this, we are adapting a vault drug-delivery system to target a bioengineered IL-2-expressing vault particle to the high-affinity IL-2R on Tregs. Following receptor-mediated endocytosis, the peptides or drugs in the vault are specifically delivered to the signaling endosome containing the IL-2R that has been activated by interaction with the IL-2-expressing drug-containing vault. This innovative technology leverages delivery of drugs via the Treg IL-2R to “dial up” Treg function to treat inflammatory diseases. If successful in the preclinical models being tested, this strategy could lead to novel treatments for autoimmune and allergic diseases.

Footer Links: