Enhancing islet and beta-cell transplant engraftment by targeting chemokine-driven inflammation

Immune cell mediated beta-cell destruction results in only 50% of islet transplant recipients remaining insulin independent at 5-years. Therapeutics targeting immune cells are successful but associated with adverse effects.

Immune cell trafficking to transplanted islets is driven by multiple chemokines, and anti-chemokine therapeutics targeting single chemokines fail. Tick evasin proteins bind multiple chemokines and potently inhibit inflammation.

Using phage-display screening followed by mutagenesis we have identified short evasin-derived peptides that inhibit multiple chemokine classes. They are highly effective against a pool of islet-expressed chemokines.

We hypothesize that neutralizing islet-expressed chemokines will ameliorate transplanted islet inflammation and beta-cell destruction. The aims of this project are to develop approaches to inhibit transplanted islet inflammation.

To achieve this, we will a) Develop novel agents (peptidomimetics and peptibodies) with enhanced potency and pharmacokinetic characteristics from our lead peptide; b) Use in vitro islet chemotaxis and islet invasion assays to assess efficacy of the novel agents; c) Use short-term animal chemotaxis and xenotransplantation assays to assess efficacy of the novel agents; d) Develop genetically engineered islets expressing novel anti-chemokine agents.

The approaches proposed are based on the innovative broad-spectrum anti-chemokine peptides discovered by us.

The application brings together expertise in T1D, islet biology and transplantation, medicinal chemistry, and chemokine/inflammation biology. In future work we will seek to validate findings in humanised mouse models before progressing to clinical studies. These approaches have transformative potential to enhance islet transplant survival and success.

The anti-chemokine approaches will also be applicable for beta-cell protection in newly diagnosed T1D.