Graft versus host disease (GvHD) is the major limitation to expanding allogeneic stem cell transplantation for the treatment of patients with hematological cancers and stem cell disorders. Acute GvHD (aGvHD) is due to the recognition of minor and major MHC disparities between the donor and host that lead to a cascade of immunological events resulting in the inflammatory state characteristic of aGvHD. Chronic GvHD (cGvHD) is a more protean manifestation of immune reactivity between donor and host, which can lead to extensive fibrotic changes in tissues, immune dysfunction and death. The pathophysiology of cGvHD is less understood compared to aGvHD partly due to the lack of informative animal models. Over the past 10 years, investigators have identified a number of new T cell lineages characterized by the activity of specific transcription factors that mediate much of the function in those cells. Of these, one of the most scrutinized has been natural regulatory T cells that express constitutively CD4 and CD25 and the transcription factor Foxp3. Treg cells can inhibit the proliferation and effector function of T and B cells in the peripheral compartment and are critical in maintaining tolerance to self-antigens. Little is known regarding how Treg cells function in vivo. Our group demonstrated that Treg cells with increased expression of L-selectin functioned best to prevent GvHD. This suggested that Treg cells function by blocking T cell activation in lymphoid tissue. However, we also published that Treg cells are required to migrate to the liver and lung to prevent GvHD occurring at those sites. How Tregs function in lymphoid tissue or parechymal organs is not clear and is the focus of this proposal.
In specific aim 1, we will focus on studies to understand how Treg cells used to prevent or treat GvHD block Teff cell function. We will use extremely novel intravital imaging of Tregs, effector T cells and antigen presenting cells in tissues such as the liver and skin to determine mechanistically how Treg interact with Teff and APCs to prevent or treat GvHD. We will investigate whether treatment of ongoing GvHD is best done using Treg cells targeted to GvHD-involved organs. An understanding of how Treg cells work is critical to inform clinical trials using Treg cells to treat or prevent aGvHD.
In specific aim 2, we will focus on a very novel finding from our laboratory that Treg cells, which do not migrate into secondary lymphoid tissue when transplanted with allogeneic bone marrow and alloreactive T cells, cause cGvHD manifested by fibrotic changes in the skin, eye and liver. This suggests that cGvHD may be due to impaired Treg function in the peripheral compartment leading to aberrant activation of donor T and B cells against host antigens that should be seen as self. We will investigate the mechanism by which CCR7 -/- Treg cells given with allogeneic bone marrow and T cells mediate cGvHD focusing on the role of donor and host T and B cells in this process. This work has the potential to alter our understanding of the mechanism by which cGvHD occurs and could offer new treatment avenues for its therapy.
Allogeneic stem cell transplantation, in which bone marrow or stem cells from a donor are transplanted into an individual with leukemia, lymphoma or diseases in which insufficient numbers of bone marrow cells are produced, can be a life-saving procedure. However, immune reactivity of donor white cells against the individual undergoing the transplant can lead to a process called graftversus- host disease (GvHD). Because the likelihood of developing GvHD is dependent on the level of the match between donors and recipients, bone marrow or stem cell transplants are only offered to individuals with a very good matched donor. This results in a significant number of eligible patients never receiving a stem cell or bone marrow transplant for they lack a suitable donor. Even when the donor and recipient are perfectly matched, GvHD is still a significant problem. Our group has focused on the use of a rare population of white cells called regulatory T cells (Treg) to prevent or treat GvHD. The current application seeks a greater understanding of how and where these cells work in the hope that this information will provide important insights into the use of these cells in patients. The second area investigated in this proposal is the theory that chronic GvHD may be due to impaired function of Treg cells in the lymphoid tissue of recipient patients. We will determine how this causes chronic GvHD in the hope that this work will provide new avenues for therapy for chronic GvHD.
| 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 |
| 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 |
| 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 ROR?t. J Immunol 189:1765-72 |
| Carlson, M J; Fulton, L M; Coghill, J M et al. (2010) L-selectin is dispensable for T regulatory cell function postallogeneic bone marrow transplantation. Am J Transplant 10:2596-603 |
