We hypothesize that a donor dendritic cell (DC) population in the rhesus macaque can be identified and purified to allow its effective employment in tolerance-enhancing strategies in renal transplantation. Using technologic approaches that we have applied successfully in humans to identify circulating (P)DCl and pDC2, we have generated preliminary data that demonstrate presumptive counterparts of these DC precursors/immature DC in the rhesus macaque.
In AIM I, we shall further characterize these cells to validate their relationship to human (and mouse) DC subsets, and to establish their influence on allogeneic T cell responses, particularly in relation to their postulated tolerogenic effects and underlying mechanisms. Use of hematopoietic growth factors (Flt3L and G-CSF) will greatly assist in addressing this Aim, Since. in vivo generated immature myeloid (M)DC presently represent the """"""""standard"""""""" tolerogenic DC, we shall compare and contrast the influence of in vivo-mobilized pDCl and pDC2 with that of their immature, in vitro-generated MDC counterparts. Based on the outcome of AIM I, we shall in AIM II, test the most promising putative tolerogenic rhesus DC subset in allogeneic recipients using established and cutting edge assays of anti- donor reactivity .We shall also investigate underlying mechanisms, in particular whether infusion of putative tolerogenic DC results in immune deviation. Although other non-exclusive mechanisms may be operative, we shall focus on the ability of rhesus DC to skew towardsTh2 predominance as immature murine DC and human pDC2 have been shown to promote this mechanism.
In AIM III, we shall work closely with our collaborators at Emory University Transplant Center and the Yerkes Primate Research Center in Atlanta. We shall test the donor DC population shown to exhibit the maximal tolerogenic potential in AIM II, in an established; MHC-mismatched rhesus renal transplantation model. Transplantation will be performed in conjunction with anti-CD40L mAb treatment of the recipient that, we hypothesize will markedly potentiate the tolerogenic effect of immature donor DC. Since deoxyspergualin has been shown recently to prevent DC maturation in rhesus renal allograft recipients in a tolerance- promoting regimen, we shall retain the option of incorporating this additional agent to further potentiate the tolerogenic action of immature donor DC combined with costimulation blockade.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI051698-03
Application #
6760908
Study Section
Special Emphasis Panel (ZAI1-PTM-I (J2))
Program Officer
Kraemer, Kristy A
Project Start
2002-07-15
Project End
2007-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
3
Fiscal Year
2004
Total Cost
$514,959
Indirect Cost
Name
University of Pittsburgh
Department
Surgery
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Ezzelarab, Mohamed B; Lu, Lien; Shufesky, William F et al. (2018) Donor-Derived Regulatory Dendritic Cell Infusion Maintains Donor-Reactive CD4+CTLA4hi T Cells in Non-Human Primate Renal Allograft Recipients Treated with CD28 Co-Stimulation Blockade. Front Immunol 9:250
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Ezzelarab, Mohamed B; Cooper, David K C; Thomson, Angus W (2015) Cell-based immunosuppression in kidney transplantation: the value of non-human primate studies. Kidney Int 88:1196-7
Rogers, Natasha M; Ferenbach, David A; Isenberg, Jeffrey S et al. (2014) Dendritic cells and macrophages in the kidney: a spectrum of good and evil. Nat Rev Nephrol 10:625-43
Morelli, Adrian E; Thomson, Angus W (2014) Orchestration of transplantation tolerance by regulatory dendritic cell therapy or in-situ targeting of dendritic cells. Curr Opin Organ Transplant 19:348-56
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