Modulation of autoimmunity to beta-cell antigens by proteases.
OBJECTIVE
Proteases are used in therapy for autoimmune diseases yet the mechanism of their action remains to be determined. We studied the immunological basis of protease therapy in the context of Type I (insulin-dependent) diabetes mellitus.


METHODS
We studied the effects of proteases (trypsin, papain, chymotrypsin, bromelain) on immune reactivity of a series of autoreactive T-cell clones from prediabetic subjects and patients with a recent onset of Type I diabetes and specific to the autoantigens GAD65, IA-2 and insulin-secretory granule protein.


RESULTS
Cell surface expression of adhesion, co-stimulatory and homing molecules on both antigen-presenting cells and T cells was changed after protease treatment. Cytokine analyses showed a selective inhibition of proinflammatory (Th-1) but not Th-2 cytokine production. Autoreactive T-cell proliferation was inhibited at pharmacological serum concentrations, whereas non-specific proliferation to phytohaemagglutinin was not affected at these concentrations. Preincubation experiments on T cells and antigen-presenting cells separately showed that this effect was mediated by APCs, but not T-cells.


CONCLUSIONS
Proteases have pleiotropic immunological effects supporting an immunomodulatory potential for the intervention of chronic inflammatory diseases and Th-1 mediated oedema formation.
Roep
B O
BO
Department of Immunohaematology and Blood Transfusion, Leiden University Medical Centre, The Netherlands. boroep@lumc.nl
van den Engel
N K
NK
van Halteren
A G S
AG
Duinkerken
G
G
Martin
S
S
D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000097:blood / Q000235:genetics; D001324:Autoantigens; D015551:Autoimmunity; D002999:Clone Cells; D003713:Dendritic Cells / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D010450:Endopeptidases / Q000378:metabolism; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology; D005968:Glutamate Decarboxylase / Q000276:immunology*; D006801:Humans; D007527:Isoenzymes / Q000276:immunology*; D008565:Membrane Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D011236:Prediabetic State / Q000276:immunology*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D013601:T-Lymphocytes / Q000276:immunology*
D015703:Antigens, CD; D001324:Autoantigens; D000939:Epitopes; D007527:Isoenzymes; D008565:Membrane Proteins; C516862:PTPRN protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D010450:Endopeptidases; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2