Development of a novel cytomedical treatment that can protect entrapped cells from host humoral immunity.
Cell therapy is expected to relieve the shortage of donors needed for organ transplantation. When patients are treated with allogeneic or xenogeneic cells, it is necessary to develop a means by which to isolate administered cells from an immune attack by the host. We have developed "cytomedicine," which consists of functional cells entrapped in semipermeable polymer, and previously reported that alginate-poly-L-lysine-alginate microcapsules and agarose microbeads could protect the entrapped cells from injury by cellular immunity. However, their ability to isolate from humoral immunity was insufficient. It is well known that the complement system plays an essential role in rejection of transplanted cells by host humoral immunity. Therefore, the goal of the present study was to develop a novel cytomedical device containing a polymer capable of inactivating complement. In the screening of various polymers, polyvinyl sulfate (PVS) exhibited high anticomplement activity and low cytotoxicity. Murine pancreatic beta-cell line (MIN6 cell) entrapped in agarose microbeads containing PVS maintained viability and physiological insulin secretion, replying in response to glucose concentration, and resisted rabbit antisera in vitro. PVS inhibited hemolysis of sensitized sheep erythrocytes (EAs) and rabbit erythrocytes by the complement system. This result suggests that PVS inhibits both the classical and alternative complement pathways of the complement system. Next, the manner in which PVS exerts its effects on complement components was examined. PVS was found to inhibit generation of C4a and Ba generation in activation of the classical and alternative pathways, respectively. Moreover, when the EAC1 cells, which were carrying C1 on the EAs, treated with PVS were exposed to C1-deficient serum, hemolysis decreased in a PVS dose-dependent manner. These results suggest that PVS inhibits C1 in the classical pathway and C3 convertase formation in the alternative pathway. Therefore, PVS may be a useful polymer for developing an anticomplement device for cytomedical therapy.
Suzuki
Ryo
R
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871, Japan.
Yoshioka
Yasuo
Y
Kitano
Etsuko
E
Yoshioka
Tatsunobu
T
Oka
Hiroaki
H
Okamoto
Takayuki
T
Okada
Naoki
N
Tsutsumi
Yasuo
Y
Nakagawa
Shinsaku
S
Miyazaki
Jun-ichi
J
Kitamura
Hajime
H
Mayumi
Tadanori
T
D000464:Alginates; D000818:Animals; D000906:Antibodies; D000917:Antibody Formation; D002460:Cell Line; D003169:Complement Inactivator Proteins / Q000276:immunology; D003165:Complement System Proteins / Q000276:immunology; D006085:Graft Survival / Q000276:immunology*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D016381:Islets of Langerhans Transplantation / Q000379:methods*; D051379:Mice; D008863:Microspheres; D011107:Polylysine / Q000031:analogs & derivatives*; D011108:Polymers / Q000737:chemistry; D012685:Sepharose
D000464:Alginates; D000906:Antibodies; D003169:Complement Inactivator Proteins; D007328:Insulin; D011108:Polymers; C051546:alginate-polylysine-alginate; D011107:Polylysine; D003165:Complement System Proteins; D012685:Sepharose