Long-term survival of segmental pancreas isografts in NOD/Lt mice treated with anti-CD4 and anti-CD8 monoclonal antibodies

• Published in: Diabetes (New York, N.Y.) Vol. 47; no. 9; pp. 1399 - 1405
• Main Authors: MOTTRAM, P. L, MURRAY-SEGAL, L. J, WENRUO HAN, MAGUIRE, J, STEIN-OAKLEY, A, MANDEL, T. E
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01-09-1998
• Subjects: AIDS/HIV; Animals; Antibodies, Monoclonal - therapeutic use; Biological and medical sciences; Care and treatment; CD4-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - immunology; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Female; Graft rejection; Graft Survival - immunology; Health aspects; Immunosuppression - methods; Insulin - biosynthesis; Islets of Langerhans - physiology; Lymphocyte Depletion - methods; Management. Various non-drug treatments. Langerhans islet grafts; Medical sciences; Mice; Mice, Inbred NOD; Monoclonal antibodies; Pancreas Transplantation - immunology; Pancreas Transplantation - pathology; Pancreas Transplantation - physiology; Pancreatic beta cell transplantation; Pancreatic beta cells; Prevention; Time Factors; Transplantation; Transplantation, Isogeneic; Type 1 diabetes; Endocrinopathy; Animal model; Diabetes mellitus; Rodentia; Homograft; Transplantation; Monoclonal antibody; Survival; Result; Vertebrata; Mammalia; Treatment; Mouse; Immunotherapy; Endocrine pancreas
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.47.9.1399

Long-term survival of segmental pancreas isografts in NOD/Lt mice treated with anti-CD4 and anti-CD8 monoclonal antibodies.
P L Mottram ,
L J Murray-Segal ,
W Han ,
J Maguire ,
A Stein-Oakley and
T E Mandel
Department of Surgery, Royal Melbourne Hospital, Parkville, Victoria, Australia. [e-mail]
Abstract
Spontaneously diabetic nonobese diabetic (NOD/Lt) mice were treated with anti-T-cell monoclonal antibodies (mAbs) at the time
of grafting with vascularized segmental pancreas isografts. Recipients were either untreated or given anti-CD4 and/or anti-CD8
mAbs (0.5 mg/20-g mouse on each of 4 consecutive days), which reduced target cell levels to <5% of normal. Graft function
was monitored by measuring blood glucose (BG) levels. Transplants were removed for histological examination when BG returned
to >20 mmol/l for two consecutive readings. Isografts from 3- to 4-week-old prediabetic mice placed in untreated diabetic
NOD mice ceased functioning in 9-13 days with a mean survival time (MST) +/- SD of 10 +/- 2. Treatment with anti-CD4 prolonged
survival significantly (MST = 61 +/- 35 days, P < 0.05 compared with untreated control mice). Anti-CD8 treatment was less
effective, but it still significantly improved graft survival (MST = 24 +/- 9 days, P < 0.05 compared with untreated control
mice). Anti-CD8 plus anti-CD4 treatment was highly effective in inhibiting autoimmune destruction of the grafts (MST = 97
+/- 8 days). This clearly demonstrates that transient inactivation of most T-cells with anti-CD4 plus anti-CD8 mAbs effectively
controls autoimmune disease in the isograft, despite recovery of CD4 and CD8 T-cells to normal levels. Although insulitis
developed in the long-term grafts, insulitis scores did not increase between 33 and 100 days, and none of the mice progressed
to IDDM in 100 days. Histology showed a predominantly peri-islet T-cell and macrophage infiltrate with ductal expression of
the cytokines interleukin (IL)-4, IL-2, and interferon-gamma. There was little infiltrate or expression of cytokines within
the islets. Thus, mAb treatment at the time of grafting allowed isograft survival and prevented progression from insulitis
to beta-cell destruction.