1,25(OH)2D3Promotes the Efficacy of CD28 Costimulation Blockade by Abatacept

Abstract Recurrence of primary focal segmental glomerulosclerosis (FSGS) occurs in up to 50% of patients after kidney transplantation and is associated with poor allograft outcome. Novel therapeutic concepts directly target podocyte function via B7-1 with inconsistent response. We present the case of a 19 yr. old patient with recurrent primary FSGS early after living donor kidney transplantation. Plasmapheresis and rituximab did not induce remission. Repetitive abatacept administration was able to achieve partial remission. Maintenance immunosuppression was subsequently switched to a belatacept-based CNI-free immunosuppression, resulting in sustained complete remission with excellent allograft function throughout a follow-up of more than 56 months.

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CD5 costimulation induces stable Th17 development by promoting IL-23R expression and sustained STAT3 activation

Blood ◽

10.1182/blood-2011-05-352682 ◽

2011 ◽

Vol 118 (23) ◽

pp. 6107-6114 ◽

Cited By ~ 36

Author(s):

Jelle de Wit ◽

Yuri Souwer ◽

Astrid J. van Beelen ◽

Rosa de Groot ◽

Femke J. M. Muller ◽

...

Keyword(s):

Th17 Cells ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Orphan Receptor ◽

The Novel ◽

Cd28 Costimulation ◽

Th17 Differentiation ◽

Novel Concept ◽

Transcription 3 ◽

Lymphocyte Receptors

Abstract IL-17–producing CD4+ T helper (Th17) cells are important for immunity against extracellular pathogens and in autoimmune diseases. The factors that drive Th17 development in human remain a matter of debate. Here we show that, compared with classic CD28 costimulation, alternative costimulation via the CD5 or CD6 lymphocyte receptors forms a superior pathway for human Th17-priming. In the presence of the Th17-promoting cytokines IL-1β, IL-6, IL-23, and transforming growth factor-β (TGF-β), CD5 costimulation induces more Th17 cells that produce higher amounts of IL-17, which is preceded by prolonged activation of signal transducer and activator of transcription 3 (STAT3), a key regulator in Th17 differentiation, and enhanced levels of the IL-17–associated transcription factor retinoid-related orphan receptor-γt (ROR-γt). Strikingly, these Th17-promoting signals critically depend on CD5-induced elevation of IL-23 receptor (IL-23R) expression. The present data favor the novel concept that alternative costimulation via CD5, rather than classic costimulation via CD28, primes naive T cells for stable Th17 development through promoting the expression of IL-23R.

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Costimulation Blockade of Both Inducible Costimulator and CD40 Ligand Induces Dominant Tolerance to Islet Allografts and Prevents Spontaneous Autoimmune Diabetes in the NOD Mouse

Diabetes ◽

10.2337/diabetes.55.01.06.db04-1154 ◽

2005 ◽

Vol 55 (1) ◽

pp. 27-33 ◽

Cited By ~ 75

Author(s):

S. A. Nanji ◽

W. W. Hancock ◽

B. Luo ◽

C. D. Schur ◽

R. L. Pawlick ◽

...

Keyword(s):

Autoimmune Diabetes ◽

Cd40 Ligand ◽

Nod Mouse ◽

Costimulation Blockade ◽

Inducible Costimulator ◽

Islet Allografts

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Interruption of OX40L signaling prevents costimulation blockade–resistant allograft rejection

JCI Insight ◽

10.1172/jci.insight.90317 ◽

2017 ◽

Vol 2 (5) ◽

Cited By ~ 7

Author(s):

William H. Kitchens ◽

Ying Dong ◽

David V. Mathews ◽

Cynthia P. Breeden ◽

Elizabeth Strobert ◽

...

Keyword(s):

Allograft Rejection ◽

Costimulation Blockade

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THU0115 The effects of costimulation blockade performed by abatacept: Decreased production of G-IFN by CD8+ T cells and of IL-17 by CD4+ T cells after in vitro stimulation in good clinical responders

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2012-eular.2080 ◽

2013 ◽

Vol 71 (Suppl 3) ◽

pp. 193.2-193

Author(s):

M. Scarsi ◽

S. Piantoni ◽

M. Chiarini ◽

C. Zanotti ◽

L. Imberti ◽

...

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Costimulation Blockade

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CD28 Costimulation Is Required for In Vivo Induction of Peripheral Tolerance in CD8 T Cells

Journal of Experimental Medicine ◽

10.1084/jem.20021429 ◽

2002 ◽

Vol 197 (1) ◽

pp. 19-26 ◽

Cited By ~ 27

Author(s):

Melanie S. Vacchio ◽

Richard J. Hodes

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Tolerance Induction ◽

Peripheral Tolerance ◽

Cd8 Cells ◽

Costimulatory Signal ◽

Cd28 Costimulation

Whereas ligation of CD28 is known to provide a critical costimulatory signal for activation of CD4 T cells, the requirement for CD28 as a costimulatory signal during activation of CD8 cells is less well defined. Even less is known about the involvement of CD28 signals during peripheral tolerance induction in CD8 T cells. In this study, comparison of T cell responses from CD28-deficient and CD28 wild-type H-Y–specific T cell receptor transgenic mice reveals that CD8 cells can proliferate, secrete cytokines, and generate cytotoxic T lymphocytes efficiently in the absence of CD28 costimulation in vitro. Surprisingly, using pregnancy as a model to study the H-Y–specific response of maternal T cells in the presence or absence of CD28 costimulation in vivo, it was found that peripheral tolerance does not occur in CD28KO pregnants in contrast to the partial clonal deletion and hyporesponsiveness of remaining T cells observed in CD28WT pregnants. These data demonstrate for the first time that CD28 is critical for tolerance induction of CD8 T cells, contrasting markedly with CD28 independence of in vitro activation, and suggest that the role of CD28/B7 interactions in peripheral tolerance of CD8 T cells may differ significantly from that of CD4 T cells.

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