Dendritic cells (DC) play a central role in defining immunologic self and peripheral tolerance. Activation or enhancement of peripheral tolerance by administration of tolerizing DC is proposed as strategy for the treatment of immune-mediated pathologies including chronic autoimmune diseases, including type 1 diabetes (T1D). Our published work, and recently those of others clearly demonstrate injection of tolerizing DC is highly effective means of preventing T1D in NOD mice. Several issues, however, need to be addressed before this approach can be safely and effectively translated into humans with or at risk for T1D. Therefore, during the R21 pre-clinical developmental phase we will; 1.) Define essential features of tolerogenic NOD DC, 2.) Determine whether tolerance induction by DC requires specific autoantigen presentation 3.) Characterize mechanisms by which NOD DC enforce peripheral tolerance, and 4.) Define genetically regulated DC maturation defects, controlled by the Iddl 0/18 diabetes susceptibility locus that partially suppress tolerogenic DC development and contribute to T1D pathogenesis. As it is our goal to translate DC-based tolerizing therapy to human T1D, we are encouraged by studies suggesting injection of DC into healthy subjects is safe and promotes regulatory T cells. Therefore, will build upon the murine studies from the R21 phase and initiate phase lb studies in patients with T1D. During the extended development phase (R33) we will; 1.) Determine the safety of injection of immature monocyte derived DC (iMoDC) into humans subjects with T 1D, 2.) Determine whether single followed by multiple injections of iMoDC pulsed with a T 1D target antigen, insulin B9-23 chain is safe, and 3.) Determine if injection of iMoDC modifies peripheral blood T cell and autoantibody responses to diabetes-related target autoantigens. The proposed studies in T1D patients will establish scientific basis and clinical experience necessary for moving DC-based therapies forward into phase 2 studies. The research team includes; M. Clare-Salzler, M.D. (PI), a diabetologist and immunologist, will direct clinical and murine studies in DC biology, genetics and mechanisms of protection, M. Atkinson, Ph.D. (Co-Investigator), will characterize T cell responses and autoantibodies, L. Moldawer, Ph.D., will provide analysis of inflammatory cytokines and DC biology, L. Morel, Ph.D., will develop and analyze new NOD congenic sublines for Idd10/18 that dysregulates NOD DC development, H. Baker, Ph.D., will characterize gene expression profiles in tolerogenic DC and congenic NOD.IddlO/]8 by high density microarray, and D. Schatz, M.D. and L. Kennedy, M.D., diabetologists, who along with Clare-Salzler will assess adverse events, diabetes management, and toxicity and safety in the R33 study.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DK063422-02
Application #
6666922
Study Section
Special Emphasis Panel (ZDK1-GRB-8 (O1))
Program Officer
Akolkar, Beena
Project Start
2002-09-30
Project End
2005-07-31
Budget Start
2003-08-01
Budget End
2005-07-31
Support Year
2
Fiscal Year
2003
Total Cost
$217,625
Indirect Cost
Name
University of Florida
Department
Pathology
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Cirillo, Piera M; Wang, Erica T; Cedars, Marcelle I et al. (2016) Irregular menses predicts ovarian cancer: Prospective evidence from the Child Health and Development Studies. Int J Cancer 139:1009-17
Cohn, Barbara A; Terry, Mary Beth; Plumb, Marj et al. (2016) Erratum to: Exposure to polychlorinated biphenyl (PCB) congeners measured shortly after giving birth and subsequent risk of maternal breast cancer before age 50. Breast Cancer Res Treat 159:591-592
Wang, Erica T; Cirillo, Piera M; Kao, Chia-Ning et al. (2013) Birth weight and childhood growth in daughters of women with irregular menstrual cycles. Gynecol Endocrinol 29:615-8
Cohn, Barbara A; Cirillo, Piera M; Sholtz, Robert I et al. (2011) Polychlorinated biphenyl (PCB) exposure in mothers and time to pregnancy in daughters. Reprod Toxicol 31:290-6
Wang, Erica T; Cirillo, Piera M; Vittinghoff, Eric et al. (2011) Menstrual irregularity and cardiovascular mortality. J Clin Endocrinol Metab 96:E114-8
Cirillo, P M; Cohn, B A; Krigbaum, N Y et al. (2011) Effect of maternal coffee, smoking and drinking behavior on adult son's semen quality: prospective evidence from the Child Health and Development Studies. J Dev Orig Health Dis 2:375-86
Cohn, Barbara A (2011) Developmental and environmental origins of breast cancer: DDT as a case study. Reprod Toxicol 31:302-11
Sholtz, Robert I; McLaughlin, Katherine R; Cirillo, Piera M et al. (2011) Assaying organochlorines in archived serum for a large, long-term cohort: implications of combining assay results from multiple laboratories over time. Environ Int 37:709-14
Mongraw-Chaffin, Morgana L; Cirillo, Piera M; Cohn, Barbara A (2010) Preeclampsia and cardiovascular disease death: prospective evidence from the child health and development studies cohort. Hypertension 56:166-71
Cohn, Barbara A; Cirillo, Piera M; Christianson, Roberta E (2010) Prenatal DDT exposure and testicular cancer: a nested case-control study. Arch Environ Occup Health 65:127-34

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