Beneficial effects of simultaneous treatment with 15-deoxyspergualin and monoclonal antibodies to CD45RB and CD154 on murine islet transplantation recipients.
BACKGROUND
Treatment of transplant recipients with either 15-deoxyspergualin (DSG) or monoclonal antibodies (mAbs) to T-cell proteins CD45RB and CD154 (a two-signal blockade) has been shown to prolong islet graft survival. Therefore, we investigated the combined effect of DSG, anti-CD45RB, and anti-CD154 in murine islet model.


METHODS
Chemically induced diabetic C57BL/6 mice underwent allografting with islets from BALB/c mice or xenografting with rat islets. After transplantation, they were treated with either DSG, the two-signal blockade, or both (the triple treatment). The tolerogenic effects of the posttransplant treatments were measured with an intraperitoneal glucose tolerance test (IPGTT), immunohistology, enzyme-linked immunosorbent assays, and flow cytometry.


RESULTS
Blood glucose profiles measured after glucose challenges were improved in all islet recipients. Enhancement of xenograft survival in triple-treated groups was not statistically significant (P = 0.08), compared to graft survival in group received only the two-signal blockade. However, 15 days after transplantation, xenografts in the triple-treated group showed a significant decrease in the proportion of CD4, CD8, and CD4CD45RB T-cells, and in the expression of interleukin-10 and interferon-gamma, relative to grafts in the other treatment groups. In addition, reduced infiltration of the xenografts by CD3 T-cells was observed in groups that had received either the two-signal blockade or the triple treatment. With long-term (>248 days) xenografts, only those in the triple-treated group were free of inflammatory infiltrates. These grafts also exhibited larger islet clusters and contained more insulin- and glucagon-positive cells, relative to grafts in the other treatment groups.


CONCLUSIONS
Triple treatment has a beneficial effect in murine islet xenotransplantation.
Jung
Da-Yeon
DY
Transplantation Research Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, Korea.
Lee
Hae-Jung
HJ
Lee
Eun-Na
EN
Lee
Jienny
J
Kim
Eun-Young
EY
Park
Hea-Jung
HJ
Chang
Chi-Young
CY
Lee
Suk-Koo
SK
Joh
Jae-Won
JW
Kwon
Ghee-Young
GY
Kim
Sung-Joo
SJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D023201:CD40 Ligand / Q000276:immunology*; D016207:Cytokines / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000601:surgery*; D005434:Flow Cytometry; D006146:Guanidines / Q000627:therapeutic use*; D007108:Immune Tolerance; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D017493:Leukocyte Common Antigens / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D051381:Rats; D013601:T-Lymphocytes / Q000276:immunology; D014183:Transplantation, Heterologous; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D016207:Cytokines; D006146:Guanidines; D007166:Immunosuppressive Agents; D023201:CD40 Ligand; D017493:Leukocyte Common Antigens; C037258:gusperimus