Nonmyeloablative bone marrow transplant offers a safe, potentially curative treatment for non-malignant hematological diseases such as sickle cell anemia. Unfortunately, successful nonmyeloablative transplant to treat sickle cell anemia has been limited due to immune-mediated graft rejection. Our research has demonstrated that rapamycin can promote regulatory T cell (Treg) differentiation of naive T cells and anergy of Th1 cells following T cell activation. We used these observations to develop a novel preparative regimen to inhibit rejection and graft versus host disease (GVHD) by promoting T cell tolerance. Our strategy reduces the frequency of alloreactive T cells with alemtuzumab, creates """"""""space"""""""" for engraftment with low dose total body irradiation, and allows lymphocyte recovery under extended rapamycin treatment. In the matched sibling setting this approach has had great success, resulting in stable mixed chimerism that corrects their hematological phenotype of sickle cell anemia and reverses pulmonary hypertension. Based on this success, a second clinical trial was developed to expand the potential donor pool to include haploidentical related donors, greatly increasing potential availability of this therapy to patients. The new trial employs the same fundamental principles in the choice of preparative regimen with the addition of dose escalation of post transplant cyclophosphamide to further reduce alloreactive T cells that could contribute to rejection or GVHD. Peripheral blood samples from patients and donors on this trial will provide a unique opportunity to systematically investigate the role of T cell tolerance in promoting stable chimerism. We propose to do this by examination of mixed lymphocyte reactions (MLRs) and intracellular cytokine staining (ICS) from samples obtained pretransplant, posttransplant on rapamycin, and posttransplant after completion of rapamycin therapy. We will determine whether the continued presence of rapamycin is necessary to suppress allogeneic responses in vitro and whether the tolerance measured in the MLR is dependent on the presence of Tregs. We will test whether addition of rapamycin or Tregs is able to suppress the MLR from a patient who develops graft rejection or GVHD while receiving rapamycin. We will determine if clinical resistance to rapamycin in the form of rejection or GVHD corresponds to biochemical resistance to rapamycin at the level of mTOR target phosphorylation and whether a novel mTOR kinase inhibitor can overcome such biochemical resistance in vitro.
A final aim i s to determine whether prolonged mTOR inhibition interferes with antigen specific T cell cytokine production or leads to generation of antigen specific Tregs to clinically relevant CMV or influenza A. We believe that a better understanding of the immunologic consequences of mTOR inhibition will result in safer and more successful bone marrow transplantation, allowing expansion of this potentially curative therapy to a wider number of patients with chronic hematologic illnesses.

Public Health Relevance

(provided by applicant): Sickle cell anemia and other chronic anemias impose a huge burden of pain and suffering for patients and large health care costs related to hospitalizations and chronic transfusion/chelation therapy. In this proposal we seek to define the operative cellular and biochemical processes that promote T cell tolerance in a novel protocol to cure sickle cell disease with non-myeloablative bone marrow transplantation. It is hoped that the results of this study will allow safer application of this curative therapy to a greater number of patients and aid in improving tolerogenic therapy for autoimmunity and solid organ transplantation as well.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI091481-02
Application #
8144889
Study Section
Special Emphasis Panel (ZAI1-PA-I (M2))
Program Officer
Hayes, Deborah
Project Start
2010-09-18
Project End
2014-08-31
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
2
Fiscal Year
2011
Total Cost
$405,900
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Patel, Chirag H; Powell, Jonathan D (2017) Targeting T cell metabolism to regulate T cell activation, differentiation and function in disease. Curr Opin Immunol 46:82-88
Bettencourt, Ian A; Powell, Jonathan D (2017) Targeting Metabolism as a Novel Therapeutic Approach to Autoimmunity, Inflammation, and Transplantation. J Immunol 198:999-1005
Chornoguz, Olesya; Hagan, Robert S; Haile, Azeb et al. (2017) mTORC1 Promotes T-bet Phosphorylation To Regulate Th1 Differentiation. J Immunol 198:3939-3948
Pollizzi, Kristen N; Sun, Im-Hong; Patel, Chirag H et al. (2016) Asymmetric inheritance of mTORC1 kinase activity during division dictates CD8(+) T cell differentiation. Nat Immunol 17:704-11
Pollizzi, Kristen N; Powell, Jonathan D (2015) Regulation of T cells by mTOR: the known knowns and the known unknowns. Trends Immunol 36:13-20
Pollizzi, Kristen N; Waickman, Adam T; Patel, Chirag H et al. (2015) Cellular size as a means of tracking mTOR activity and cell fate of CD4+ T cells upon antigen recognition. PLoS One 10:e0121710
Delgoffe, Greg M; Powell, Jonathan D (2015) Feeding an army: The metabolism of T cells in activation, anergy, and exhaustion. Mol Immunol 68:492-6
Delgoffe, Greg M; Powell, Jonathan D (2015) Sugar, fat, and protein: new insights into what T cells crave. Curr Opin Immunol 33:49-54
Pollizzi, Kristen N; Patel, Chirag H; Sun, Im-Hong et al. (2015) mTORC1 and mTORC2 selectively regulate CD8? T cell differentiation. J Clin Invest 125:2090-108
Lee, Chen-Fang; Lo, Ying-Chun; Cheng, Chih-Hsien et al. (2015) Preventing Allograft Rejection by Targeting Immune Metabolism. Cell Rep 13:760-770

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