Site-Specific Nanofiber-Coated Regulatory T Cells for the Induction of Tolerance in Vascularized Composite Allotransplants
Abstract
Objectives and Rationale: Vascularized composite allotransplantation (VCA) from a deceased donor has emerged as effective treatment to correct injuries that result in loss of limb and/or disfigurement sustained by both armed Service personnel and civilians alike. However, a major drawback of VCA is the need for lifelong treatment with anti-rejection drugs. These medicines are costly and have severe side effects, including toxicity to kidneys and an increased rate of infections, cancers, diabetes and hypertension. Therefore, there has been great interest in inducing immunologic tolerance, a state where the recipient’s immune system recognizes the transplant as “self.” Establishment of such a condition can eliminate the need for anti-rejection drugs. Injections of donor stem cells that result in a partial or full replacement of the recipient’s immune system with that of the donor (chimerism) is the only successful tolerance-inducing approach to date. However, it is associated with multiple complications. However, a crucial discovery was made in these tolerant human patients – all had developed an increase in their white blood cells called regulatory T cells (Tregs). Also, studies in animals have shown that infusions of Tregs can induce immunologic tolerance. Therefore, another possible approach is to inject the recipient with Tregs. Since these Tregs are normally few in numbers, we and others have expanded them and tested them in patients. Thus, we have successfully tested the safety of infusions of 0.5-, 1.0- and 5-billion expanded Tregs, and we will soon test the efficacy of in 120 kidney recipients. For Treg therapy to be most effective, the cells need to migrate to the transplant. Normally, cells including Tregs are attracted to the transplant by the increased inflammation, as well as by biological agents secreted from the graft. Since these can also attract harmful rejection-causing immune cells, we also need to devise methods that favor Tregs over the harmful cells. This proposal tries to achieve just that. We propose to coat the Tregs with synthetic products we call nanofibers and then use the coated Tregs in mouse models of hind-limb transplantation. These nanofibers will have built-in structures that we propose will take the Tregs to the transplant. We will test whether the nanofiber-coated Tregs as site-specific Tregs are more effective than uncoated Tregs in reaching the limb transplant to prevent injury and inducing tolerance. The Plan: Our long-term goal is to develop tolerance procedures that will lead to reduction or withdrawal of antirejection drug treatment in human VCA. Since large numbers of human VCA subjects are not available, we will test our hypothesis in this proposal using animal models and under three headings, scientifically called Specific Aims. Specific Aim 1. To determine whether nanofiber coated Tregs preferentially home to sites of inflammation, such as a limb transplant. We will infuse different numbers of Tregs that uncoated or coated with three different types of nanofibers and then check for the infused Tregs in the limb transplant. This is to investigate what number of Tregs are needed and which nanofiber is better at taking the Tregs to the transplant. After finding out the best, we will use that Treg number in all subsequent studies. Specific Aim 2. To evaluate the functionality and efficacy of the PA-nanofiber coated Tregs in promoting peripheral nerve repair or regeneration. There are a number of reports that Tregs can repair severed nerve, such as in a transplant. We will investigate whether and which nanofiber-coated Tregs will better repair the nerves that are being cut during the limb transplant surgery. Specific Aim 3. To determine whether PA-nanofiber coated regulatory T cells mitigate hind-limb allograft rejection and promote tolerance induction; this is most important portion of this grant proposal. Normally, a limb transplant from one stra
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110862
Entities
People
- Zheng Jenny Zhang
Organizations
- Northwestern University
- United States Army