Abstract
Uncoated spherical hydrogel microspheres (calcium alginate, nominal
M(r) exclusion of > 600 kD) 800-900 microns in diameter were employed
to prevent immune rejection of discordant islet xenografts isolated
from pigs and cows. The islets were immobilized in the microspheres
and injected into the peritoneum of 14 nonimmunosuppressed streptozotocin
(STZ)-induced diabetic C57BL/6J mice. Four recipients received islet
grafts from bovine calves, and 10 received islet grafts from pigs.
In the control group of 15 diabetic mice implanted with nonencapsulated
islets, 6 received i.p. porcine islets and 5 received i.p. bovine
islets, whereas remaining 4 received porcine islets under the kidney
capsule. Plasma glucose concentrations in recipients of the alginate-encapsulated
islets promptly dropped from a preimplantation value of 498 +/- 47
(mean +/- SEM) to 142 +/- 6 (bovine) and 178 +/- 7 mg/dl (porcine)
during the first wk. All the animals sustained these levels for at
least 1 mo. Two mice implanted with bovine islets subsequently reverted
to diabetes (plasma glucose > 250 mg/dl) at 43 days postimplantation.
The remaining grafts maintained function for > 10 wk. In contrast,
nonencapsulated islets failed to function, or sustained euglycemia
for < 4 days. Mice receiving encapsulated islets showed a 23-38%
gain in body weight during the first mo after implantation, compared
with < 1% (P < 0.002) and 32% (P = 0.84) for the untreated diabetic
(n = 6) and normal control (n = 6) groups. Immunohistochemical staining
of long-term grafts (> 10 wk) revealed viable islets, with well-granulated
alpha, beta, and delta cells; the external surfaces of the microreactors
were free of fibrotic overgrowth and exhibited only occasional host
cell adherence. Uptake studies with IgG and thyroglobulin (M(r) of
669 kD) suggest that the microreactors were permeable to molecules
with a molecular weight of up to > 600 kD (including the various
proteins of the complement system, M(r) of 24-570 kD). Spheres implanted
in the peritoneum after only 1 wk stained positive for both IgG and
for the C3 component of complement. These findings suggest that prolonged
survival of discordant xenografts of porcine and bovine islets in
the STZ diabetic mouse model can be achieved with uncoated alginate
microspheres that are permeable to IgG and complement. The question
of whether similar results can be achieved with uncoated alginate
microspheres in higher animals remains to be fully determined.
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