Lymphocytic infiltration and immune activation in metallothionein promoter-exendin-4 (MT-Exendin) transgenic mice.
Glucagon-like peptide 1 (GLP-1) exhibits considerable potential for the treatment of type 2 diabetes because of its effects on stimulation of insulin secretion and the inhibition of gastric emptying, appetite, and glucagon secretion. However, native GLP-1 undergoes rapid enzymatic inactivation, prompting development of long-acting degradation-resistant GLP-1 receptor agonists such as exendin-4 (Ex-4). To study the consequences of sustained exposure to Ex-4, we generated metallothionein promoter-exendin-4 (MT-Exendin) mice that continuously express a proexendin-4 transgene in multiple murine tissues. We now report that MT-Exendin mice develop extensive tissue lymphocytic infiltration with increased numbers of CD4(+) and CD8a(+) cells in the liver and/or kidney and increased numbers of B220(+) cells present in the pancreas and liver. MT-Exendin mice generate antibodies directed against Ex-4, exendin NH(2)-terminal peptide (ENTP), and proexendin-4 as well as antibodies that cross-react with native GLP-1. Furthermore, lymphocytes isolated from MT-Exendin mice proliferate in response to proexendin-4 but not after exposure to Ex-4 or ENTP. These findings demonstrate that expression of a proexendin-4 transgene may be associated with activation of humoral and cellular immune responses in mice.
Baggio
Laurie L
LL
Department of Medicine, Banting and Best Deabetes Centre, Toronto General Hospital, 200 Elizabeth St., MBRW4R-402, Toronto, Ontario, Canada M5G2C4.
Holland
Dianne
D
Wither
Joan
J
Drucker
Daniel J
DJ
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D000077270:Exenatide; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000276:immunology; D000067757:Glucagon-Like Peptide-1 Receptor; D007114:Immunization; D007150:Immunohistochemistry; D007668:Kidney / Q000166:cytology / Q000276:immunology; D017493:Leukocyte Common Antigens / Q000276:immunology; D008099:Liver / Q000166:cytology / Q000276:immunology; D008214:Lymphocytes / Q000166:cytology / Q000276:immunology*; D008264:Macrophages / Q000166:cytology / Q000276:immunology; D008297:Male; D008668:Metallothionein / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010179:Pancreas / Q000166:cytology / Q000276:immunology; D010455:Peptides / Q000235:genetics* / Q000276:immunology / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000235:genetics*; D018027:Receptors, Glucagon / Q000502:physiology; D014688:Venoms / Q000235:genetics* / Q000276:immunology
C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D008668:Metallothionein; D000077270:Exenatide; D017493:Leukocyte Common Antigens