Allogeneic bone marrow transplantation (allo-BMT) is a potent form of immunotherapy with a potential for curing many hematological diseases through its graft-versus-leukemia/tumor effect (GVL). However, graft-versus-host disease (GVHD), the most frequent and severe complication of allo-BMT has limited the application of this effective therapy. Several lines of evidence have established a critical role for donor na?ve conventional cells (Tcon) in the induction, and to donor natural T regulatory cells (Tregs) in the regulation of GVHD. Nevertheless, there are significant gaps in our understanding of the molecular mechanisms that dampen Tcon cells and simultaneously enhance Treg functions. Recent data have demonstrated that microRNAs (miRs), a class of small, noncoding RNAs, play a significant role in orchestrating immune responses. The role of these critical molecular regulators in the modulation of allo-T cell responses in GVHD and GVL has heretofore been unexplored. Exciting preliminary data generated by us show that the overall miR landscape, and specifically miR-142, is significantly altered in dendritic cells (DCs) and alloreactive T cells. T better decipher these novel observations, we have generated miR-142 knock-out (KO) mice and observed that miR-142 deficiency in donor T cells mitigated GVHD. In this proposal we will build on our exciting preliminary observations and test the central premise that deficiency of miR-142 will reduce GVH responses through impairment of donor Tcon cells and enhancement of donor Treg functions. Utilizing complementary approaches with miR-142 knock-out (KO) mice and blockade with novel locked nucleic acid (LNA) oligonucleotide we will systematically test the cell autonomous role and function of miR-142 in Tcon and Treg cells after allo-BMT. If successful, our proposal will lead to targeting of miRs, specifically miR-142, as a novel strategy for prevention of GVHD and may also be salutary in a broad array of immune mediated diseases.
The specific aims are:
Specific Aim (SA) 1: To determine the role of miR-142 expression in donor derived na?ve T conventional cells (Tcon) in the induction of GVH responses after allogeneic BMT. We will test the hypothesis that deficiency of miR-142 in na?ve Tcons will impair their functions and reduce the severity of GVH responses.
Specific Aim (SA) 2: To analyze the role of miR-142 in the negative regulation of GVHD by the donor derived natural Foxp3+ T regulatory cells (Tregs) after allogeneic BMT. We will explore the hypothesis that deficiency of miR-142 in donor derived Tregs will enhance their GVHD protective effects. Together, the above studies will illuminate a novel, heretofore unexplored role of miR mediated molecular regulation of GVH responses. If successful, may lead to innovative therapeutic strategies targeting miR-142 to impair Tcon responses or enhance Treg responses. Such an approach may prove to be beneficial in a broad array of many other T cell mediated immune diseases.

Public Health Relevance

Allogeneic bone marrow transplantation (BMT) is a potentially curative therapy for a number of malignant and non-malignant diseases. However, the application of this effective therapeutic modality has been impeded by its most frequent and severe complication, acute graft-versus-host disease (GVHD). Donor derived T lymphocyte subsets, the na?ve alloreactive and the natural CD4+Foxp3+ T cells cause and mitigate GVHD, respectively. The molecular mechanisms underpinning their functions in causing GVHD are not well- understood. Micro-RNAs (miRs) are small, evolutionarily conserved noncoding RNAs that function as molecular rheostats for controlling the magnitude of immune responses. Their role in regulating T cell responses and GVHD following allogeneic BMT is not known. We have recently identified a novel miR, miR-142, as an important regulator of immune responses. Our proposal aims to understand the underlying mechanisms of miR142 mediated regulation of donor T cell subsets after allogeneic BMT and to determine whether it can be targeted to mitigate the severity of GVHD. If successful, this could pave way for the validation and development of a novel molecular target for reducing GVHD and thus make allogeneic BMT safer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA173878-01A1
Application #
8516684
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Mccarthy, Susan A
Project Start
2013-03-01
Project End
2018-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
1
Fiscal Year
2013
Total Cost
$322,663
Indirect Cost
$115,163
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Toubai, Tomomi; Hou, Guoqing; Mathewson, Nathan et al. (2014) Siglec-G-CD24 axis controls the severity of graft-versus-host disease in mice. Blood 123:3512-23