Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement

The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.


Altered Programmed Death 1-Programmed Death Ligand 1 (PD-1-PD-L1) Pathway in T Cells of (New Zealand Black New Zealand White) BWF1 Mice with Anti-PD-1 Antibody

Wong,  Maida, La Cava,  Antonio, Singh,  Ram P., Hahn,  Bevra H.

Purpose:

PD1-PD-L1 pathway is reportedly a costimulatory pathway that regulates self-tolerance by providing negative signals to T cells, resulting in anergy and decreased cytotoxicity. We have shown that induction of suppressive CD8+ T cells (CD8+Treg) by administration of an artificial anti-DNA Ig-based synthetic peptide pConsensus (pCons), reduces PD-1 expression on the suppressor cells, which have increases in expression of Foxp3 and production of TGF-b. Also, untolerized mice treated with anti-PD-1 have delayed onset of proteinuria and increased survival compared to unmanipulated mice. We therefore studied the kinetics of PD-1 expression in CD8+Tregin vivo, as they moved from permissive to suppressive following administration of pCons to BWF1 lupus-prone mice.

Method:

Antibody against PD-1 or control isotype-matched IgG were injected into naïve vs. tolerized BWF1 mice intraperitoneally. TGF-b, IFN-g, IL-6, IL-17A, anti-dsDNA and total IgG production were assessed by flow cytometry and/or ELISA.

Results:

In anti-PD1-treated mice, serum anti-dsDNA, IgG and IFN-g production were reduced compared to unmanipulated controls; the low production was comparable to the levels in tolerized mice. In contrast, anti-PD-1-treated mice had increased TGF-b expression in the serum; they failed to develop the elevations in serum IL-6 and IL-17A levels and proteinuria that are characteristic of the unmanipulated BWF1 controls.

Conclusion:

PD-1 is likely one of the core participants in inherent autoreactivity of T cells and in the mechanisms of immune tolerance in our model. Blocking PD-1 in otherwise unmanipulated mice delays autoantibody production, nephritis and mortality for many weeks; it prevents the increase in pro-inflammatory IL-6, IFN-g and IL-17A while increasing secretion of anti-inflammatory TGF-b. Such a pattern could result from the ability of PD-1 to participate in suppression of Th17 cells, either directly or by activation of Treg. Complete silencing of PD-1 with siRNA eliminates suppressive capacity of CD8+Treg. In functional suppressive CD8+Treg from tolerized micei, PD-1 is down-regulated, but not to zero. We conclude that the interplay between Th1, Th17 and Treg cells depends in part on fine tuning of the expression of PD-1.

To cite this abstract, please use the following information:
Wong, Maida, La Cava, Antonio, Singh, Ram P., Hahn, Bevra H.; Altered Programmed Death 1-Programmed Death Ligand 1 (PD-1-PD-L1) Pathway in T Cells of (New Zealand Black New Zealand White) BWF1 Mice with Anti-PD-1 Antibody [abstract]. Arthritis Rheum 2009;60 Suppl 10 :1030
DOI: 10.1002/art.26107

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