Alpha CD 2 mAb treatment safely attenuates adoptive transfer colitis.
Increased proliferation, defective apoptosis, and cytokine dysregulation of T lymphocytes are thought to be important for the pathogenesis of inflammatory bowel disease. Since these phenomena can be corrected by alpha CD 2 mAb, we asked whether CD2 directed immunotherapy safely prevents and/or ameliorates adoptive transfer colitis. Colitis was induced by transfer of CD4(+) T cell blasts to syngenic RAG 1(-/-) mice or CD 45 RB(high) CD4(+) T cells to SCID mice. The alpha CD 2 mAb 12-15 or rat IgG was given, starting either initially or upon first signs of colitis. Disease activity was assessed by clinical monitoring, microscopic scoring, hemoccult, endoscopy, and blood count analysis. Cytokine production of stimulated LPL was measured by ELISA and cell proliferation by [(3)H]-thymidine incorporation. Parasite control was analyzed in a murine model of infection with Toxoplasma gondii. The alpha CD 2 mAb significantly increased mean survival time when starting at transfer of blasts (survival >35 days: alpha CD 2 69% vs 0% of controls, P<0.001). In the SCID colitis model hematochezia and macroscopic colitis were delayed. When used in established T-cell blast colitis, the benefit was less pronounced, even in combination with dexamethasone (mean survival+/-s.e.m.: alpha CD 2+dexa: 13.5+/-2.9 vs dexa+IgG: 6.3+/-1.0, P<0.05). In the preventive experiment the alpha CD 2 mAb markedly reduced IL-2 secretion and T-cell proliferation. The immune response towards Toxoplasma gondii was not impaired. These studies show for the first time that CD2 directed immunotherapy can attenuate or delay adoptive transfer colitis and ameliorate established colitis. Most likely inhibition of IL-2 secretion and T-cell proliferation are responsible for these effects. Still, immune defence towards T. gondii is maintained.
Pawlowski
Nina N
NN
Medizinische Klinik I, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.
Kakirman
Hacer
H
Kühl
Anja A
AA
Liesenfeld
Oliver
O
Grollich
Katja
K
Loddenkemper
Christoph
C
Zeitz
Martin
M
Hoffmann
Jörg C
JC
D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal; D015703:Antigens, CD / Q000276:immunology; D018801:CD2 Antigens / Q000276:immunology*; D049109:Cell Proliferation; D005260:Female; D005434:Flow Cytometry; D015212:Inflammatory Bowel Diseases / Q000209:etiology / Q000276:immunology / Q000628:therapy*; D007376:Interleukin-2 / Q000096:biosynthesis; D008214:Lymphocytes / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000276:immunology / Q000473:pathology; D014123:Toxoplasmosis / Q000628:therapy
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018801:CD2 Antigens; D007376:Interleukin-2