title: Long-term survival of segmental pancreas isografts in NOD/Lt mice treated with anti-CD4 and anti-CD8 monoclonal antibodies.
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.
authors.affiliation: Department of Surgery, Royal Melbourne Hospital, Parkville, Victoria, Australia. p.mottram@medicine.unimelb.edu.au
authors.forename: P L
authors.initials: PL
authors.lastname: Mottram
authors.forename: L J
authors.initials: LJ
authors.lastname: Murray-Segal
authors.forename: W
authors.initials: W
authors.lastname: Han
authors.forename: J
authors.initials: J
authors.lastname: Maguire
authors.forename: A
authors.initials: A
authors.lastname: Stein-Oakley
authors.forename: T E
authors.initials: TE
authors.lastname: Mandel
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D006085:Graft Survival / Q000276:immunology*; D007165:Immunosuppression Therapy / Q000379:methods*; D007328:Insulin / Q000096:biosynthesis; D007515:Islets of Langerhans / Q000502:physiology; D008212:Lymphocyte Depletion / Q000379:methods*; D051379:Mice; D016688:Mice, Inbred NOD; D016035:Pancreas Transplantation / Q000276:immunology* / Q000473:pathology / Q000502:physiology; D013997:Time Factors; D014185:Transplantation, Isogeneic
chemical_list: D000911:Antibodies, Monoclonal; D007328:Insulin