Immunoregulatory effects of allogeneic mixed chimerism induced by nonmyeloablative bone marrow transplantation on chronic inflammatory arthritis and autoimmunity in interleukin-1 receptor antagonist-deficient mice.
OBJECTIVE
To investigate the immunoregulatory effects of allogeneic mixed chimerism induced by T cell-depleted, nonmyeloablative bone marrow transplantation (BMT) on chronic inflammatory arthritis and autoimmunity in mice deficient in interleukin-1 receptor antagonist (IL-1Ra).


METHODS
IL-1Ra(-/-) mice (H-2K(d)) were treated with antibody to asialoganglioside G(M1) (anti-natural killer cell), total body irradiation (500 cGy), and T cell-depleted, nonmyeloablative BMT derived from C57BL/6 mice (H-2K(b)). Engraftment and chimerism were evaluated in peripheral blood, lymph nodes, and spleen by multicolor flow cytometry. The severity of arthritis was evaluated by clinical scoring and histopathologic assessment. Levels of IgG1 and IgG2a subtypes of anti-type II collagen (anti-CII) antibodies were measured in serum samples. After T cells were stimulated with CII, ovalbumin, and phytohemagglutinin, T cell proliferative responses and levels of cytokine production (interferon-gamma [IFNgamma], tumor necrosis factor alpha [TNFalpha], interleukin-10 [IL-10], and IL-17) were assayed in culture supernatants.


RESULTS
All IL-1Ra(-/-) mice receiving BMT showed marked improvement in arthritis within 3 weeks, as well as successful induction of mixed chimerism. These mice showed higher levels of IgG1, and lower levels of IgG2a anti-CII antibodies and weaker T cell proliferative responses than did mice in the control groups (either no treatment or conditioning alone without bone marrow rescue). In mixed chimeras, the levels of IFNgamma, TNFalpha, and IL-17 produced from CII-stimulated T cells were significantly suppressed and IL-10 production was significantly higher as compared with controls.


CONCLUSIONS
The introduction of allogeneic mixed chimerism showed a strong immunoregulatory potential to correct established chronic inflammatory arthritis and autoimmunity originating from a dysregulated proinflammatory cytokine network.
Cho
Seok Goo
SG
St. Mary's Hospital, Catholic University of Korea, Seoul.
Min
So-Youn
SY
Park
Min Jung
MJ
Lee
Kyung Wha
KW
Cho
Young-Gyu
YG
Cho
Mi-La
ML
Chang
Hong Seok
HS
Park
Se-Ho
SH
Lee
Jong Wook
JW
Min
Woo Sung
WS
Kim
Chun Choo
CC
Kim
Ho-Youn
HY
D000818:Animals; D001168:Arthritis / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D001323:Autoantibodies / Q000097:blood; D015551:Autoimmunity / Q000276:immunology*; D016026:Bone Marrow Transplantation / Q000276:immunology*; D046528:Chimerism; D002908:Chronic Disease; D024043:Collagen Type II / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D053590:Interleukin 1 Receptor Antagonist Protein; D020381:Interleukin-17 / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D012795:Sialoglycoproteins / Q000172:deficiency*; D013601:T-Lymphocytes / Q000276:immunology; D014184:Transplantation, Homologous; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D001323:Autoantibodies; D024043:Collagen Type II; C507764:Il1rn protein, mouse; D007074:Immunoglobulin G; D053590:Interleukin 1 Receptor Antagonist Protein; D020381:Interleukin-17; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma