Differences in suppressor of cytokine signaling-1 (SOCS-1) expressing islet allograft destruction in normal BALB/c and spontaneously-diabetic NOD recipient mice.
BACKGROUND
The ability to block interferon signaling represents an important strategy in designing therapies to prevent beta-cell destruction during islet allograft rejection.


METHODS
The SOCS proteins regulate cytokine signaling by blocking activation of JAK/STAT proteins. Using islets isolated from SOCS-1 transgenic mice (SOCS-1-Tg; these mice express SOCS-1 under the control of the human insulin promoter and are on the C57BL6/J background), we investigated whether SOCS proteins can prevent the destruction pancreatic islet cells transplanted beneath the kidney capsule of major histocompatibility complex mismatched normal BALB/c and spontaneously-diabetic NOD mouse recipients.


RESULTS
Immunohistochemical staining for insulin confirmed the presence of donor SOCS-1-Tg islets in islet allografts harvested at 22 days posttransplant, whereas grafts of control non-Tg islets were destroyed by 14 days. In contrast, SOCS-1-Tg allogeneic islets were not protected from beta-cell destruction in clinically diabetic NOD mice. The islet allografts functioned for 1 week posttransplant; however, hyperglycemia returned after 2 weeks and the grafts were destroyed. Rejection of SOCS-1-Tg and non-Tg islets in autoimmune diabetic NOD mice was associated with an infiltrate of both CD4+ and CD8+ T cells and a T2-type cytokine response (IL-4) rather than the conventional T1-type cytokine response observed during islet allograft rejection. Self-antigen upregulation in response to IFN-gamma stimulation did not appear to be a factor in rejection of the islet allografts.


CONCLUSIONS
These results demonstrate that expression of SOCS-1 in islets delays islet allograft rejection but cannot circumvent destruction of the islets by the recurrence of the tissue-specific autoimmune process of spontaneous diabetes.
Solomon
Michelle
M
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Flodström-Tullberg
Malin
M
Sarvetnick
Nora
N
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics*; D016207:Cytokines / Q000502:physiology*; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000601:surgery; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006084:Graft Rejection / Q000473:pathology / Q000517:prevention & control*; D016381:Islets of Langerhans Transplantation / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D012097:Repressor Proteins / Q000235:genetics*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014184:Transplantation, Homologous / Q000473:pathology
D001786:Blood Glucose; D002352:Carrier Proteins; D016207:Cytokines; D012097:Repressor Proteins; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins