Exogenous Heat Shock Protein gp96 Ameliorates CD4+CD62L+ T-Cell-mediated Transfer Colitis.

[severe combined immunodeficiency]

The heat shock protein gp 96 is an endoplasmic reticulum chaperone involved in endoplasmic reticulum stress reactions . gp 96 binds antigens and is secreted into extracellular space on cell stress . After reinternalization by antigen presenting cells , antigens can be transferred to major histocompatibility complex molecules . In recent studies , we found induction of gp 96 during differentiation of intestinal macrophages , whereas it was absent in intestinal macrophages of patients with Crohn 's disease .To study immuno-modulating effects of gp 96 in T -cell transfer colitis BALB /c donor mice were injected with 2 × 100 μg gp 96 . After 1 week , 2 .5 × 10 CD 4 CD 6 2 L cells were isolated from spleens and injected into severe combined immunodeficiency recipients . Another group received cells from untreated donors and was treated with 100 μg gp 96 after transfer . Control groups received cells from untreated donors , or buffer alone .After transfer of CD 4 CD 6 2 L T cells from gp 96 -pretreated donors , mice (TBT gp 96 ) showed an initial weight loss , but after 3 weeks , they recovered and reached the starting weight after 5 weeks . Mice treated with gp 96 after transfer (TAT gp 96 ) showed a delayed weight loss in comparison with the CD 4 CD 6 2 L group . The histological scores in CD 4 CD 6 2 L mice were 2 .6 ± 0 .1 , in TBT gp 96 mice 1 .3 ± 0 .3 (CD 4 CD 6 2 L versus TBT gp 96 : P < 0 .05 ) and in mice treated after transfer 1 .9 ± 0 .1 (CD 4 CD 6 2 L versus TAT gp 96 : P < 0 .05 ).These findings indicate an essential role of gp 96 in the maintenance of tolerance against luminal antigens in the intestinal mucosa . The absence of gp 96 in intestinal macrophages of patients with Crohn 's disease might provoke loss of this tolerance mediating mechanism .