Treatment of adjuvant-induced arthritis by oral administration of mycobacterial Hsp65 during disease.
OBJECTIVE
Oral administration of antigen prior to disease induction has been shown to induce peripheral tolerance in several experimental autoimmune diseases. However, the clinical benefit of pretreatment with antigens is limited. The aim of this study was to investigate whether adjuvant-induced arthritis (AIA) could be treated by oral administration of mycobacterial heat-shock protein 65 (Hsp65) during ongoing disease.


METHODS
AIA was induced in Lewis rats by immunization with Mycobacterium tuberculosis in Freund's incomplete adjuvant. Oral feeding of Hsp65 in the presence or absence of soybean trypsin inhibitor (SBTI) was started on day 11 after immunization. Arthritis was monitored visually, and joint pathology was examined radiologically.


RESULTS
Oral treatment with Hsp65 during ongoing disease significantly reduced the activity of AIA. However, treatment with Hsp65 was only successful when SBTI was coadministered to prevent breakdown of the Hsp65. The beneficial effect of Hsp65/SBTI treatment during AIA was also represented by a clear reduction of articular destruction, as visualized by radiography. Moreover, feeding Hsp65/SBTI resulted in a lower number of both spleen and mesenteric lymph node (MLN) cells expressing the costimulatory molecule CD80 (B7-1). The number of cells expressing CD86 (B7-2) was not altered. Furthermore, MLN cells from AIA animals treated with Hsp65/SBTI contained a lower number of T cells expressing the activation marker CD134 (Ox-40). In addition, treatment with Hsp65/ SBTI was accompanied by an increased proliferative response of spleen cells to the Hsp65 antigen in vitro. Moreover, Hsp65/SBTI-treated rats showed less Hsp65-specific interferon-gamma and increased production of interleukin-10.


CONCLUSIONS
Ongoing AIA activity can be reduced by oral administration of Hsp65 only when protein breakdown in the gastrointestinal tract is inhibited.
Cobelens
P M
PM
Wilhelmina Children's Hospital of the University Medical Center Utrecht, The Netherlands.
Heijnen
C J
CJ
Nieuwenhuis
E E
EE
Kramer
P P
PP
van der Zee
R
R
van Eden
W
W
Kavelaars
A
A
D000284:Administration, Oral; D000818:Animals; D000942:Antigens, Bacterial / Q000008:administration & dosage; D015703:Antigens, CD / Q000096:biosynthesis; D001169:Arthritis, Experimental / Q000188:drug therapy*; D018122:B7-1 Antigen / Q000096:biosynthesis; D051940:B7-2 Antigen; D001426:Bacterial Proteins / Q000627:therapeutic use; D018834:Chaperonin 60; D018833:Chaperonins / Q000008:administration & dosage*; D016207:Cytokines / Q000187:drug effects / Q000502:physiology; D007108:Immune Tolerance / Q000187:drug effects; D007596:Joints / Q000187:drug effects; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D010940:Plant Proteins; D051381:Rats; D011917:Rats, Inbred Lew; D030262:Soybean Proteins; D013025:Glycine max; D013601:T-Lymphocytes / Q000276:immunology; D014360:Trypsin Inhibitor, Kunitz Soybean / Q000494:pharmacology; D014361:Trypsin Inhibitors / Q000494:pharmacology
D000942:Antigens, Bacterial; D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D001426:Bacterial Proteins; C497966:Cd86 protein, rat; D018834:Chaperonin 60; D016207:Cytokines; D008562:Membrane Glycoproteins; D010940:Plant Proteins; D030262:Soybean Proteins; D014361:Trypsin Inhibitors; C074119:heat-shock protein 65, Mycobacterium; C018411:trypsin inhibitor, Miles soybean; D014360:Trypsin Inhibitor, Kunitz Soybean; D018833:Chaperonins