Organ transplantation is an accepted therapy for various end-stage organ diseases. Systemic immunosuppression is required to prevent immunologic rejection in transplanted allografts. However, side- effects such as infections, cancers, and metabolic derangements are among the list of complications that organ transplant recipients suffer while on the necessary organ saving immunosuppressant medication. While significant advancements have been made with the design and efficacy of newer immunosuppressive medications, many carry heightened systemic risk profiles. In particular, rapamycin, has been shown to be an effective immunosuppressant, but carries an increased risk of infection, wound healing problems and metabolic side-effects1. Recent studies have shown that utilization of sub-therapeutic doses of rapamycin (insufficient to inhibit graft rejectin) combined with a systemic increase in ex-vivo expanded, adoptively transferred regulatory T cells (Treg) may prevent graft rejection2. These seminal studies suggest that combined low dose rapamycin with standard immunosuppressive care may prolong graft survival by inducing the recipient's immune system to `self-immunosuppress'. A potential way to further circumvent the systemic side-effects of rapamycin administration is to develop strategies to specifically deliver rapamycin directly to the grafted tissues. Many of the priming events that lead to the development of an alloimmune response have been shown to occur at the level of the graft3. Thus, while current practice utilizes systemic immunosuppression to modulate host immunity there is a growing appreciation that immune suppression at the graft level may have more profound effects on alloimmunity whilst sparing the recipient from the complications of systemic immunosuppression. Here, we propose to use novel graft targeting self-assembling micelle nanoparticles to attenuate both acute and chronic rejection. To facilitate graft targeting, we will conjugate these Targeted Rapamycin Micelles (TRaM) to soluble recombinant complement receptor 2 (CR2), a targeting moiety we have extensively characterized4. CR2 binds to long lived cleavage fragments of complement protein C3 (iC3b, C3dg, and C3d), which we have shown to deposit in cardiac allografts early post-transplantation as a response to ischemia- reperfusion injury, an unavoidable event in all solid organ transplants5. In addition to rapamycin loading and CR2 targeting moiety coating, micelles will contain near infrared (NIR) fluorophores for homing and tracking imaging studies. The feasibility of CR2 mediated targeting has previously been demonstrated and successful delivery of complement regulatory proteins utilizing this targeting moiety has been achieved6. By utilizing the novel targeting capabilities o CR2 we will be able to deliver rapamycin directly to the grafted organ. We hypothesize that rapamycin may be packaged within a biologically inert nanoparticle, tracked, targeted to, and released at the level of a transplanted allograft as a means for drug delivery and local immunosuppression.
The necessary immunosuppressant medications required to prevent organ transplant rejection carry with them a host of harmful systemic side-effects and are currently delivered in an untargeted manner. Our group has identified a powerful nanoparticle device and targeting moiety to specifically deliver rapamycin at the level of the organ allograft. These novel Targeted Rapamycin Micelles (TRaM) address the glaring problems of global immunosuppression and lack of operational tolerance whilst setting the stage for future systems of therapeutic targeting and delivery in transplantation.
|Cheng, Qi; Patel, Kunal; Lei, Biao et al. (2018) Donor pretreatment with nebulized complement C3a receptor antagonist mitigates brain-death induced immunological injury post-lung transplant. Am J Transplant 18:2417-2428|
|Tran, Danh T; Esckilsen, Scott; Mulligan, Jennifer et al. (2018) Impact of Mitochondrial Permeability on Endothelial Cell Immunogenicity in Transplantation. Transplantation 102:935-944|
|Patel, Kunal; Atkinson, Carl; Tran, Danh et al. (2017) Nanotechnological Approaches to Immunosuppression and Tolerance Induction. Curr Transplant Rep 4:159-168|
|Zhu, Peng; Esckilsen, Scott; Atkinson, Carl et al. (2016) A simplified cuff technique for abdominal aortic transplantation in mice. J Surg Res 200:707-13|
|Nadig, Satish N (2016) Transplant Arteriosclerosis. Transplantation 100:2249-2250|