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Effective suppression of donor specific antibody production by Cathepsin S inhibitors in a mouse transplantation model.

Abstract：

:Donor-specific antibodies (DSA) are a major risk factor for antibody-mediated rejection (ABMR) in solid organ transplantation, and ABMR remains a medical challenge. Therefore, effective anti-ABMR therapies are needed to improve overall graft survival. Cathepsin S (Cat S) is an essential protease for antigen peptide loading onto lysosomal/endosomal major histocompatibility complex (MHC) class II molecules to promote antigen presentation. Cat S deficiency produces immuno-deficient phenotypes including a suppressed humoral immune response, and Cat S inhibition reportedly prevents autoimmunity. However, little is known about the effects of Cat S inhibitors on organ transplantation, especially ABMR. Here, we report the pharmacological profile of novel Cat S inhibitors, AS2761325 and AS2863995, and explore their preventive potential on DSA production and acute rejection in a mouse cardiac transplantation model. Cat S inhibitors potently inhibited upregulation of antigen peptide loading MHC class II expression on the surface of splenic B cells and suppressed ovalbumin-induced T cell-dependent antibody production in mice. In a mouse cardiac transplantation model, oral administration of AS2761325 monotherapy inhibited DSA production without affecting graft survival. When combined with a suboptimal dose of tacrolimus, AS2761325 significantly prolonged graft survival. The more potent Cat S inhibitor AS2863995 also prolonged graft survival and almost completely suppressed DSA production. These results suggest that Cat S inhibitors may be promising ABMR prophylaxis drug candidates. Combination therapy comprising a Cat S inhibitor and calcineurin inhibitors may be a more effective immunosuppressive maintenance therapy for controlling both cell-mediated and antibody-mediated rejection.

journal_name

Eur J Pharmacol

journal_title

European journal of pharmacology

authors

Kubo K,Kawato Y,Nakamura K,Nakajima Y,Nakagawa TY,Hanaoka K,Oshima S,Fukahori H,Inami M,Morokata T,Higashi Y

doi

10.1016/j.ejphar.2018.09.007

subject

Has Abstract

pub_date

2018-11-05 00:00:00

pages

145-152

eissn

0014-2999

issn

1879-0712

pii

S0014-2999(18)30524-7

journal_volume

838

pub_type

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Effective suppression of donor specific antibody production by Cathepsin S inhibitors in a mouse transplantation model.