PREVENTION OF GRAFT-VERSUS-HOST DISEASE AND THE INDUCTION OF TRANSPLANT TOLERANCE BY LOW-DOSE UV-B IRRADIATION OF BM CELLS COMBINED WITH CYCLOSPORINE IMMUNOSUPPRESSION
Oa. Ohajekwe et al., PREVENTION OF GRAFT-VERSUS-HOST DISEASE AND THE INDUCTION OF TRANSPLANT TOLERANCE BY LOW-DOSE UV-B IRRADIATION OF BM CELLS COMBINED WITH CYCLOSPORINE IMMUNOSUPPRESSION, Transplantation, 60(12), 1995, pp. 1510-1516
GVHD is prevented and stable chimerism is induced in the rat EMT model
by 700 J/m(2) but not 100-500 J/m(2) W-B irradiation of allogeneic BM
cells. Paradoxically, CsA which prevents GVHD in clinical BMT causes
an aggressive autoimmune disease termed syngeneic GVHD in irradiated s
yngeneic BMT recipients after its withdrawal. Recently, we have shown
that while 500-700 J/m(2) UV-E irradiation of syngeneic BM cells combi
ned with a 30-day course of CsA recipient immunosuppression impairs he
mopoiesis due to lack of hemopoietic factors, a low dose of 100-300 J/
m(2) W-B is effective in preventing CsA-induced autoimmune disease wit
hout endangering BM engraftment. This study extends these findings to
the P-to-F-1 hybrid and fully allogeneic rat BMT models and examines t
he effectiveness of low-dose W-B irradiation of BM cells combined with
a short course of CsA treatment in the prevention of GVHD and inducti
on of transplant tolerance. Lethally gamma-irradiated (10.5 Gy) LBNF(1
) recipients of naive or W-B irradiated (100-700 J/m(2)) BMT were trea
ted with CsA (12.5 mg/kg/day) for 30 consecutive days after BMT. All l
ethally irradiated LENF(1) that did not receive BMT died in <16 days,
while animals transplanted with W-B (700 J/m(2)) BMT survived >1 year
without GVHD. In contrast, all recipients of naive BMT died of lethal
GVHD in <50 days. Similarly, all recipients of naive BMT that received
a 30-day course of CsA therapy developed severe GVHD with 60% mortali
ty after cessation of CsA therapy. CsA-treated recipients of BMT irrad
iated with 700 J/m(2) died between 12 and 25 days from failure of hemo
poiesis. In contrast, CsA-treated recipients of 100-200 J/m(2) W-B irr
adiated BMT showed full BM engraftment without GVHD after cessation of
CsA and survived >1 year. These results were reproducible in the full
y allogeneic UV-B BMT model. To test for donor-specific tolerance, the
animals challenged 100 days after BMT with cardiac allografts accepte
d permanently (>100 days) Lewis but not BN (non-BMT parental donor) ca
rdiac allografts. Our results confirm that 700 J/m(2) W-B irradiation
of BM cells combined with CsA recipient immunosuppression impairs the
recovery capacity of stem cells while the use of lower W-B (100-200 J/
m(2)) is effective in preventing CsA-induced autoimmune disease withou
t endangering BM engraftment and leads to induction of transplant tole
rance.