Allograft Homing and Function of Regulatory T Cells Post-Transplant

Children'S Hosp Of Philadelphia, Philadelphia PA

Investigators

Linked publications & trials

Abstract

Aim 1: Test whether the CCR7 pathway has a key role in determining the development of host alloresponses. While much work points to the importance of CC7 and its ligands in regulating DC and naive T cell homing to secondary lymphoid tissues, previous studies in CCR7-/- recipients failed to identify any significant role in determining allograft survival. However, on exploring this area we shown a key role for the CCR7 pathway in determining the fate of islet allografts. We will expand upon these studies using mice deficient in CCR7-/- or the CCR7 chemokine ligands ELC (CCL19) and SLC (CCL21). We will seek confirmation of the importance of CCR7 targeting (as would be relevant to therapeutic use in higher mammals) by production and use of CCL19.lg fusion protein in wild-type allograft recipients, as well as through the application of anti-mCCR7 antibodies and CCR7-directed small molecules. As a further proof of principle we will also test whether mice with targeted deletions of CCX-CKR, a newly described CCL19- scavenging receptor, so as to assess whether long-term allograft survival can be achieved in the presence of increased levels of CCR7 ligands. Aim 2: Understand the role of the CCR4 chemokine pathway in regulating Treg function within secondary lymphoid tissues as well as allografts. We will study the upregulation of CCR4 upregulation by Tregs, the extent that CCR4 differs from other relevant chemokine receptors (including CCR6 and CCR8), how CCR4+ Tregs function within secondary lymphoid tissues and how they migrate to allografts. They studies will utilize CCR4-/- mice and mice deficient in either CCR4 ligand, TARC (CCL17) and MDC (CCL22) to determine whether chemokine gradients leading to recruitment of CCR4+ Tregs to allografts are a result of host or donor cell production. We will also seek to confirm the importance of our data in wild-type mice using CCR4-blocking small molecules. Lastly, we will seek to understand the functions of intragraft Tregs in two ways. First, we will build on our preliminary data indicating that Treg recruitment to an allograft leads to local upregulation of ILT3, which can then play a role in further modulate host T cell responses. Secondly, we will undertake re-transplant studies since our initial data indicate that intragraft Tregs can promote tolerance in naive recipients through chemokine-dependent mechanisms. Except in the context of profound leukocyte depletion, allografts are infiltrated by host leukocytes that can cause acute or chronic rejection, or simply persist within grafts or can mediate allograft tolerance. Our studies will dissect the means by Treg cell are exert their effects on host T cells both within secondary lymphoid tissues and within allografts. We expect the data generated from this project will have diagnostic, prognostic and therapeutic significance in clinical Tx.