Expression of immunoregulatory molecules by thyrocytes protects nonobese diabetic-H2h4 mice from developing autoimmune thyroiditis.
One approach to prevent tissue destruction by autoimmune attack in organ-specific autoimmune diseases is to protect the target tissue from autoimmune reaction, regardless of its persistent activity. To provide proof-of-principle for the feasibility of this approach, the immunoregulatory molecules, TNF-related apoptosis-inducing ligand (TRAIL) and indoleamine 2, 3-dioxygenase, were expressed in the thyroid glands using adenovirus vector in nonobese diabetic-H2(h4) mice that spontaneously develop thyroiditis. Mice were anesthetized, and the thyroid glands were exposed by neck dissection, followed by in situ infection with adenovirus vector (5 x 10(10) particles per mouse) twice or thrice, starting 1 d or 4 wk before mice were supplied with sodium iodine (NaI) water. After 8 wk NaI provision, the extent of thyroiditis, serum titers of antithyroglobulin antibodies, and cytokine expression in the spleen were examined. In situ infection of adenovirus expressing TRAIL or indoleamine 2, 3-dioxygenase, but not green fluorescent protein, significantly suppressed thyroiditis scores. However, antithyroglobulin antibody titers and expression levels of cytokines (interferon-gamma and IL-4) in the spleen remained unaltered. Importantly, adenovirus infection 4 wk after NaI provision was also effective at suppressing thyroiditis. The suppressive effect of TRAIL appears to be mediated at least partly by accumulation of CD4(+)Foxp3(+) regulatory T cells into the thyroid glands. Thus, localized expression of immunoregulatory molecules efficiently protected the thyroid glands from autoimmune attack without changing the systemic autoimmunity in nonobese diabetic-H2(h4) mice. This kind of immunological intervention, although it does not suppress autoimmune reactivity, may have a potential for treating organ-specific autoimmune diseases.
Nakahara
Mami
M
Department of Medical Gene Technology, Divisions of ClinicalPharmaceutics, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Nagayama
Yuji
Y
Saitoh
Ohki
O
Sogawa
Rintaro
R
Tone
Shigenobu
S
Abiru
Norio
N
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D019610:Cytoprotection / Q000235:genetics / Q000276:immunology; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D007155:Immunologic Factors / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D009928:Organ Specificity / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D013961:Thyroid Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D013967:Thyroiditis, Autoimmune / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*
D016207:Cytokines; D007155:Immunologic Factors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D053221:TNF-Related Apoptosis-Inducing Ligand