Session Time: 3:15pm-4:00pm
Presentation Time: 3:30pm-4:00pm
*Purpose: Complications from long-term use of calcineurin inhibitors remain a major issue for transplant patients and alternative therapies are needed. The clinical efficacy of CTLA4-Ig (Belatacept) remains dissatisfactory. However, there is clear evidence that its immunomodulatory effect is enhanced by concomitant inhibition of proinflammatory mediators (i.e. enhanced costimulation blockade). We investigated the combination of CTLA4-Ig with novel injectable peptidic hydrogels, which provide controlled release of the JAK inhibitor Tofacitinib (Tofa) at the graft site, for solid organ and vascularized composite allotransplantation.
*Methods: We optimized a method for making peptidic hydrogels containing Tofa crystals (Tofa-Hydro). We used a BALB/c into C57BL/6 heart transplant model to assess the impact of combination therapy and Tofa-Hydro localization on graft survival. We used an orthotopic hind-limb transplant model to investigate activity of matrix metalloproteinases (MMPs) during rejection. Systemic Tofa concentration was detected using liquid chromatography-mass spectrometry. MMPs activity in vivo was detected using live animal imaging (IVIS) with MMPs-activatable probes.
*Results: Tofa-Hydro releases Tofa over a period of 7-10 days. A one-time application of Tofa-Hydro in the area surrounding the transplanted heart (combined with systemic CTLA4-Ig) renders long-term graft survival (MST=127 days vs CTLA4-Ig-only MST=36 days, P<0.05). Importantly, application of Tofa-Hydro to a distal site ablates this synergistic improvement of survival, demonstrating the localized effect of Tofa-Hydro. No appreciable levels of systemic Tofa were found when using Tofa-Hydro in either injection site. We further developed MMPs-sensitive hydrogels with the goal of achieving delivery of Tofa as a function of MMPs activity in VCA. Enzyme-based degradation of these new hydrogels was confirmed in vitro. IVIS analysis of hind-limb transplants shows early appearance of MMPs activity that peaks on POD 11 and is localized at the graft, supporting the applicability of protease-sensitive hydrogels.
*Conclusions: Hydrogel-based Tofa delivery in combination with CTLA4-Ig provides a significant extension of transplant survival reducing the risk of side effects derived from systemic exposure. Tuning the release of Tofa to MMPs activity, via injectable MMPs-sensitive hydrogels, has the potential to fine-tune its localized synergism with CTLA4-Ig and achieve a more profound modulation of rejection.
To cite this abstract in AMA style:Komin A, Liang C, Majumder P, Calderon-Colon X, Tiburzi O, Lozano MIglesias, Zhang Y, Brandacher G, Patrone J, Schneider J, Raimondi G. A Novel Injectable Hydrogel-Based Approach to Localize and Tune the Actuation of Enhanced Costimulation Blockade to the Strength of Transplant Rejection [abstract]. Am J Transplant. 2020; 20 (suppl 3). https://atcmeetingabstracts.com/abstract/a-novel-injectable-hydrogel-based-approach-to-localize-and-tune-the-actuation-of-enhanced-costimulation-blockade-to-the-strength-of-transplant-rejection/. Accessed March 8, 2021.
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