Allogeneic stem cell transplantation (Allo-SCT) is still the most effective form of therapy for the treatment of patients with high risk or relapsed acute leukemia, bone marrow failure syndromes, congenital bone marrow production defects, and is increasingly used as a potential curative therapy for patients with low grade lymphoid malignancies. Allo-SCT is limited in most transplant centers to the treatment of individuals with a perfect or one antigen HLA mismatch with the donor because of the high risk of acute GvHD found after greater mismatched transplants. Even with prophylactic therapy, the incidence of acute GvHD is 30-70%. Additionally, the treatment of acute GvHD has not changed markedly in thirty years and consists primarily of glucocorticoids, which are associated with a significant number of side-effects and complications. Our group has been interested in a new approach to the prevention or treatment of acute GvHD. This approach targets the early activation of donor T cells that occurs in recipient lymphoid tissue and is mediated by interactions with host antigen presenting cells. This interaction mediates both the activation and proliferation of donor T cells. We have found that the chemokine receptor, CCR7, expressed by donor T cells is critically important for the migration of donor T cells to lymph nodes and the interaction of those T cells with APCs in the spleen. Blocking the function of CCR7 prevented acute GvHD without interfering with the anti-tumor properties mediated by donor T cells. This has led our group to isolate pharmacological compounds that block the activity of CCR7 as an approach to prevent or treat GvHD. Thus, we are not targeting the migration of T cells to GvHD target organs mediated by a large number of chemokine ligands/receptors but the migration of naive T cells to secondary lymphoid tissue, which is mediated specifically by CCR7. Over the past 18 months, we have identified four compounds that block the function and signaling of both human and murine CCR7. We have preliminary data presented in this proposal that our lead compounds, R71921a and b, can prevent acute GvHD in a haploidentical transplant model and that this activity is similar to that found using the drug tacrolimus. This proposal is focused on determining if these inhibitors and two other compounds can prevent GvHD without inhibiting the anti-tumor or anti-infective properties of donor T cells and to determine the mechanism by which these compounds function. Additional studies will determine if our lead compounds can treat ongoing acute GvHD, can enhance the function of calcineurin inhibitors, and do not impact on the ability of regulatory T cells to prevent acute and chronic GvHD. If these studies are successful, we will pursue, in a separate proposal, evaluations of the human CCR7 inhibitors in canine studies of allo-SCT. The overall goals of this work are to develop these inhibitors as a potential new therapy for the prevention or treatment of acute GvHD. We believe that targeting CCR7 may offer the """"""""holy grail"""""""" approach sought by transplant investigators for over 30 years by preventing acute GvHD while preserving the GvL response.
GvHD remains the biggest barrier to the wider adoption of allogeneic SCT as a therapy. Our work focuses on a novel group of compounds that can block GvHD by targeting the chemokine receptor, CCR7. Successful completion of this proposal would lead to a phase I/II clinical trial of these compounds.
|Lin, Kaifeng Lisa; Fulton, LeShara M; Berginski, Matthew et al. (2014) Intravital imaging of donor allogeneic effector and regulatory T cells with host dendritic cells during GVHD. Blood 123:1604-14|
|Dubovsky, Jason A; Flynn, Ryan; Du, Jing et al. (2014) Ibrutinib treatment ameliorates murine chronic graft-versus-host disease. J Clin Invest 124:4867-76|
|Allen, Jessica L; Tata, Prasanthi V; Fore, Matthew S et al. (2014) Increased BCR responsiveness in B cells from patients with chronic GVHD. Blood 123:2108-15|
|Fulton, LeShara M; Taylor, Nicholas A; Coghill, James M et al. (2014) Altered T-cell entry and egress in the absence of Coronin 1A attenuates murine acute graft versus host disease. Eur J Immunol 44:1662-71|
|Flynn, Ryan; Du, Jing; Veenstra, Rachelle G et al. (2014) Increased T follicular helper cells and germinal center B cells are required for cGVHD and bronchiolitis obliterans. Blood 123:3988-98|
|Alexander, Kylie A; Flynn, Ryan; Lineburg, Katie E et al. (2014) CSF-1-dependant donor-derived macrophages mediate chronic graft-versus-host disease. J Clin Invest 124:4266-80|
|Coghill, James M; Fowler, Kenneth A; West, Michelle L et al. (2013) CC chemokine receptor 8 potentiates donor Treg survival and is critical for the prevention of murine graft-versus-host disease. Blood 122:825-36|
|Aoyama, Kazutoshi; Saha, Asim; Tolar, Jakub et al. (2013) Inhibiting retinoic acid signaling ameliorates graft-versus-host disease by modifying T-cell differentiation and intestinal migration. Blood 122:2125-34|
|Fulton, LeShara M; Carlson, Michael J; Coghill, James M et al. (2012) Attenuation of acute graft-versus-host disease in the absence of the transcription factor RORÎ³t. J Immunol 189:1765-72|
|Serody, Jonathan S; Hill, Geoffrey R (2012) The IL-17 differentiation pathway and its role in transplant outcome. Biol Blood Marrow Transplant 18:S56-61|