BACKGROUNDMacrophage-colony stimulating factor (M-CSF) has been implicated in HIV neuropathogenesis through its ability to modulate activation of macrophages (MΦs) and microglia, as well as enhance the susceptibility of these cells to infection and promote virus production. We have recently reported that MΦs accumulating perivascularly and within nodular lesions in archival brain tissue of simian immunodeficiency virus (SIV)-infected rhesus macaques with encephalitis (SIVE) express M-CSF. In contrast, IL-34, which shares the same receptor, cFMS, was observed more often in parenchymal cells.METHODSFrontal white and grey matter from non-infected and SIV-infected rhesus macaques with and without SIVE were examined by single- and double-label immunohistochemistry for M-CSF, IL-34, and CD163 expression. Primary rhesus macaque and human peripheral blood mononuclear cells were cultured with and without 2.5 ng/ml M-CSF or IL-34 alone and with 470 nM or 4.7 μM of GW2580, a receptor tyrosine kinase inhibitor with high specificity for cFMS. After 24 h, cells were analyzed by flow cytometry to examine the effect of these cytokines on promoting an M2 monocyte/MΦ phenotype.RESULTSHere, we demonstrate that in SIVE brain, accumulating M-CSF(+) MΦs are also CD163(+), while IL-34 does not appear to co-localize significantly with CD163 in the parenchyma. We further demonstrate that M-CSF and IL-34 are expressed by neurons in normal brain but are altered in SIV and SIVE. Through in vitro studies, we show that M-CSF and IL-34 upregulate CD163, a marker for type 2 activation of MΦs (M2), by primary monocytes, which is attenuated by the addition of GW2580.CONCLUSIONSTogether, these data suggest that both cFMS ligands may promote and/or prolong M2 activation of MΦs and microglia in brains of SIV-infected animals with encephalitis. As such, cFMS signaling may be an attractive target for eliminating long-lived MΦ reservoirs of HIV infection in brain, as well as other tissues.

01 Oct 2015·Journal of Clinical InvestigationQ1 · MEDICINE

IL-34 is a Treg-specific cytokine and mediates transplant tolerance

Q1 · MEDICINE

Article

Author: Jason Ossart ; Laurent Tesson ; Elodie Picarda ; Claire Usal ; Séverine Bézie ; Ignacio Anegon ; Karine Renaudin ; Carole Guillonneau

Cytokines and metabolic pathway-controlling enzymes regulate immune responses and have potential as powerful tools to mediate immune tolerance. Blockade of the interaction between CD40 and CD40L induces long-term cardiac allograft survival in rats through a CD8+CD45RClo Treg potentiation. Here, we have shown that the cytokine IL-34, the immunoregulatory properties of which have not been previously studied in transplantation or T cell biology, is expressed by rodent CD8+CD45RClo Tregs and human FOXP3+CD45RCloCD8+ and CD4+ Tregs. IL-34 was involved in the suppressive function of both CD8+ and CD4+ Tregs and markedly inhibited alloreactive immune responses. Additionally, in a rat cardiac allograft model, IL-34 potently induced transplant tolerance that was associated with a total inhibition of alloantibody production. Treatment of rats with IL-34 promoted allograft tolerance that was mediated by induction of CD8+ and CD4+ Tregs. Moreover, these Tregs were capable of serial tolerance induction through modulation of macrophages that migrate early to the graft. Finally, we demonstrated that human macrophages cultured in the presence of IL-34 greatly expanded CD8+ and CD4+ FOXP3+ Tregs, with a superior suppressive potential of antidonor immune responses compared with non-IL-34-expanded Tregs. In conclusion, we reveal that IL-34 serves as a suppressive Treg-specific cytokine and as a tolerogenic cytokine that efficiently inhibits alloreactive immune responses and mediates transplant tolerance.

01 Jul 2013·Journal of Interferon & Cytokine ResearchQ4 · MEDICINE

Elevated Serum and Synovial Fluid Levels of Interleukin-34 in Rheumatoid Arthritis: Possible Association with Disease Progression via Interleukin-17 Production

Q4 · MEDICINE

Article

Author: Xia, Liping ; Tian, Ye ; Lu, Jing ; Shen, Hui

To measure the levels of interleukin-34 (IL-34) in serum and synovial fluid (SF) of patients with rheumatoid arthritis (RA) and to evaluate the effect of recombination human (rh) IL-34 on IL-17 production by peripheral blood mononuclear cells (PBMC) in RA patients, the serum and SF levels of IL-34, and the production of IL-17 by rhIL-34-treated PBMC of RA patients were measured by enzyme-linked immunosorbent assay. We also tested the change of IL-34 level after tumor necrosis factor (TNF)-α blockade therapy in 30 RA patients. In contrast to almost no detectable IL-34 in osteoarthritis (OA) and healthy serum, IL-34 could be detected in 93 out of the 125 RA cases (74.4%). Sera IL-34 levels were significantly higher in RA patients compared with the controls and correlated with disease activity. IL-34 levels were higher in SF samples than in sera in 11 RA patients. The level of serum IL-34 decreased after anti-TNF treatment. In the presence of rhIL-34, stimulation of PBMC from RA patients resulted in increased production of IL-17. These findings suggest that IL-34 may play a role in the pathogenesis of RA.

100 Deals associated with FPT-025

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Indication	Highest Phase	Country/Location	Organization	Date
Infectious Diseases	Discovery	US	Five Prime Therapeutics, Inc.	-
Inflammation	Discovery	US	Five Prime Therapeutics, Inc.	-
Neoplasms	Discovery	US	Five Prime Therapeutics, Inc.	-

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