Pl. Mottram et al., Transgenic anti-CD4 monoclonal antibody secretion by mouse segmental pancreas allografts promotes long term survival, TRANSPL IMM, 8(3), 2000, pp. 203-209
To compare the effectiveness of transgenic and systemic monoclonal antibody
therapy for pancreas transplantation, vascularised segmental pancreas allo
grafts from wild-type or transgenic pancreatic tissue that secreted monoclo
nal anti-CD4 were placed in CBA recipients in which diabetes had been induc
ed chemically by streptozotocin (STZ, non-autoimmune diabetes). In untreate
d CBA recipients, wild-type BALB/c or C57BL/6 bm1 pancreas transplants were
rejected in a mean survival time (MST) of 27 and 30 days, respectively. BA
LB/c and C57BL/6 graft survival improved when recipients were given a short
course of T cell depleting monoclonal anti-CD4 antibody, (GK 1.5, 2 mg tot
al on days -1, 0, 1, 2 with grafting on day 0) with MST +/- S.D. of 71 +/-
29 and 44 +/- 36 days, respectively. Thus, transient depletion of CD4 was e
ffective in delaying pancreas allograft rejection in these strain combinati
ons. The use of C57BL/6 bm1 mice transgenic for a rat anti-CD4 antibody (GK
5 mice) as pancreas donors provided allografts that secreted sufficient ant
i-CD4 antibody to cause CD4 T cell depletion in the recipients (CD4 cells d
ecreased from 30 to < 5% of small lymphocytes). This degree of depletion wa
s not sustained and the CD4 recovery inversely correlated with graft surviv
al. Mice with > 20% CD4 cells in the splenic lymphocyte population 4 weeks
post-transplant rejected their grafts (3 of 10 mice). However, in 7 of 10 m
ice CD4 cells remained low(< 15%) and allografts survived for > 80 days. Th
e GK5 allografts survived significantly longer than those from non-transgen
ic bm1 controls (MST 83 +/- 32 days, compared with 30 days, P < 0.0005). Th
is survival time was similar to that of BALB/c allografts in CBA recipients
treated with a high dose of anti-CD4 antibody. Thus, transgenic secretion
of anti-CD4 antibody by the pancreas allograft was very effective in prolon
ging its survival. (C) 2000 Elsevier Science B.V. All rights reserved.