ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 140

Inhibition of Cathepsin S Leads to Suppression of SS-a/SS-B Specific T Cells from Patients with Primary Sjøgren Syndrome

Patrick Hargreaves1,2, Michel Theron1, Fabrice Kolb1, Marianne Manchester1, Bernhard Reis1, Andre Tiaden2, Diego Kyburz2 and Tobias Manigold2, 1Hoffmann La Roche, Basel, Switzerland, 2Rheumatology, University Hospital Basel, Basel, Switzerland

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: ,

Session Information

Date: Sunday, October 21, 2018

Title: T Cell Biology and Targets in Autoimmune and Inflammatory Disease Poster

Session Type: ACR Poster Session A

Session Time: 9:00AM-11:00AM

Background/Purpose: Primary Sjögren syndrome (pSS) is an autoimmune disease characterised by an infiltration of T and B cells into exocrine gland tissue and its subsequent destruction. Antigen presenting cells, including B cells, foster T cell activation and anti-SS-A/SS-B producing plasma cells, eventually leading to disease progression and systemic complications.
Cathepsin S (CatS) is crucially involved in MHCII processing in pSS mouse models and patients. In this translational study we investigated the ex vivo effects of the CatS inhibitor RO5459072 in different bio-compartments, including specific T cells, of pSS patients and healthy controls.
Methods: Ex vivo CatS activity was assessed in different bio-compartments of 15 pSS patients and 13 healthy controls and in presence or absence of RO5459072 using commercial activity and quantification assays. In addition, antigen (5µg/mL SS-A, 5µg/mL SS-B, 5µg/mL Influenza H3N2; 2µg/mL Tetanus Toxoid and 100ng/mL SEB) specific T cell responses were examined using 2×105 PBMC/well IFN-g/IL-17 Dual ELISPOT (48h incubation) and 5×104 PBMC/well BrdU proliferation assays after (72h incubation) in presence or absence of RO5459072.
Results: pSS patients showed significantly higher CatS activity in tear fluid than healthy controls (two-tailed t-test p<0.01). RO5459072 significantly suppressed CatS activity in tears of pSS patients (two-tailed t-test p<0.01). CatS inhibition also exerted a strong and dose-dependent suppression of T cell responses towards SS-A and SS-B antigen in ex vivo derived pSS patient cells in Elispot and BrdU assays (Table 1).

Conclusion: CatS activity in tear fluid seems to be a relevant biomarker for pSS disease activity. RO5459072 is a potent inhibitor of CatS and the pSS associated relevant antigen specific T cell responses.

Table 1. Suppression of antigen specific T cell responses (Elispot) and suppression of cell proliferation (BrdU) in the presence of RO5450972 (1-100 µM).

Elispot – SFU/Million Cells (mean of triplicates)

 

SS-A

SS-B

SEB

RO5450972

0µM

1µM

10µM

100µM

0µM

1µM

10µM

100µM

0µM

100µM

pSS 1

80

46.7

38.3*

41.7*

111.7

55

31.7

18.33

>1000

>1000

pSS 2

258.3

230

60*

23.3*

105

130

63.3

25*

>1000

>1000

pSS 12

30

23.3

15

6.7

73.3

38.3**

35**

33.3

>1000

>1000

pSS 15

23.3

18.3

15

3.9*

40

21.7

13.3

4.5

>1000

>1000

BrdU – Stimulation Index (mean of triplicates)

 

SS-A

SS-B

SEB

RO5450972

0µM

1µM

10µM

100µM

0µM

1µM

10µM

100µM

0µM

100µM

pSS 3

1.405

1.617

1.598

0.363**

1.89**

1.978

2.505

0.991**

4.207****

0.924***

pSS 4

1.211*

1.301

1.085

0.329***

1.968*

1.86

1.255

0.473**

1.92*

0.238*

pSS 7

1.867*

1.806

1.769

1.008*

2.838**

2.568

1.749

0.95**

8.70**

2.841**

pSS 11

1.348

1.426

1.393

0.391**

1.932*

1.85

2.233

1.268*

6.711*

2.507*

 

IFN-g Spot Forming Units (SFU) were determined using an CTL Elispot reader. Results from unstimulated control conditions were subtracted from antigen specific results and expressed as SFU/Million PBMC and statistical analyses were applied. BrdU results are expressed as a Stimulation index, where absorbance results of the antigen condition is divided by the result of the untreated control the BrdU assay. One-tailed t-test, * p<0.05, ** p<0.01, ***p<0.001, ****p<0.0001

 

 

Disclosure: P. Hargreaves, Hoffmann La Roche, 2, 3; M. Theron, Hoffmann La Roche, 3; F. Kolb, Hoffmann La Roche, 3; M. Manchester, Hoffmann La Roche, 3; B. Reis, Hoffmann La Roche, 3; A. Tiaden, Hoffmann La Roche, 2; D. Kyburz, Hoffmann La Roche, 2; T. Manigold, Hoffmann La Roche, 2.

To cite this abstract in AMA style:

Hargreaves P, Theron M, Kolb F, Manchester M, Reis B, Tiaden A, Kyburz D, Manigold T. Inhibition of Cathepsin S Leads to Suppression of SS-a/SS-B Specific T Cells from Patients with Primary Sjøgren Syndrome [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 9). https://acrabstracts.org/abstract/inhibition-of-cathepsin-s-leads-to-suppression-of-ss-a-ss-b-specific-t-cells-from-patients-with-primary-sjogren-syndrome/. Accessed .

« Back to 2018 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/inhibition-of-cathepsin-s-leads-to-suppression-of-ss-a-ss-b-specific-t-cells-from-patients-with-primary-sjogren-syndrome/