Short course single agent therapy with an LFA-3-IgG(1) fusion protein prolongs primate cardiac allograft survival

被引:54
作者
Kaplon, RJ
Hochman, PS
Michler, RE
Kwiatkowski, PA
Edwards, NM
Berger, CL
Xu, H
Meier, W
Wallner, BP
Chisholm, P
Marboe, CC
机构
[1] COLUMBIA UNIV COLL PHYS & SURG,DEPT SURG,NEW YORK,NY 10032
[2] COLUMBIA UNIV COLL PHYS & SURG,DEPT PATHOL,NEW YORK,NY 10032
[3] BIOGEN INC,CAMBRIDGE,MA 02142
关键词
D O I
10.1097/00007890-199602150-00004
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
The interaction of T cell costimulatory molecules with their ligands is required for optimal T cell activation, Interference with such interactions can induce antigen unresponsiveness and delay xeno- and allograft rejection. We have previously shown that LFA3TIP, a soluble human lymphocyte function-associated antigen (LFA)-3 construct, binds CD2 and inhibits responses of human T cell in vitro. This study reports the first use of a human fusion protein, LFA3TIP, to significantly prolong primate cardiac allograft survival. Based on our observation that LFA3TIP inhibits baboon allogeneic mixed lymphocyte reactions, we gave baboon recipients of heterotopic cardiac allografts injections of LFA3TIP, 3 mg/kg i.v., for 12 consecutive days, starting 2 days before transplantation. This regimen delayed graft rejection fi om an average of 10.6+/-2.3 days for human IgG-treated controls (n=5) to an average of 18.0+/-5.3 days for LFA3TIP-injected animals (n=7; P less than or equal to 0.01). Grafts from LFA3TIP-treated animals showed markedly diminished coronary endothelialitis as compared with control animals. LFA3TIP reached peak serum levels of approximately 100 mu g/ml after 7-9 injections and persisted in the 10-mu g/ml range for 1 to 2 weeks after the final injection. Despite these blood levels, circulating antibodies to LFA3TIP were not detected in the serum, No renal or hepatic toxicity was noted. The possible mechanism by which LFA3TIP acts to inhibit graft rejection is discussed; success in prolonging graft survival when LFA3TIP is used as a single-agent therapy suggests great potential for this novel therapeutic agent.
引用
收藏
页码:356 / 363
页数:8
相关论文
共 36 条
[1]   MONOCLONAL-ANTIBODIES AGAINST HUMAN T-CELL ADHESION MOLECULES - MODULATION OF IMMUNE FUNCTION IN NONHUMAN-PRIMATES [J].
BERLIN, PJ ;
BACHER, JD ;
SHARROW, SO ;
GONZALEZ, C ;
GRESS, RE .
TRANSPLANTATION, 1992, 53 (04) :840-849
[2]   PREPARATION, CHARACTERIZATION, AND PRIMATE TESTING OF MONOCLONAL ANTI-THYMOCYTE GLOBULIN [J].
BIEBER, CP ;
HOWARD, FD ;
PENNOCK, J ;
WONG, J ;
SHORTHOUSE, R ;
STINSON, EB .
TRANSPLANTATION, 1981, 31 (04) :283-289
[3]  
Chisholm P L, 1994, Ther Immunol, V1, P205
[4]  
COSIMI AB, 1990, SURGERY, V108, P406
[5]  
COSIMI AB, 1990, J IMMUNOL, V144, P4604
[6]  
COSIMI AB, 1984, TRANSPL P, V16, P1459
[7]  
DAMLE NK, 1992, J IMMUNOL, V148, P1985
[8]   VARIATION IN PATIENT RESPONSE ASSOCIATED WITH DIFFERENT PREPARATIONS OF MURINE MONOCLONAL-ANTIBODY THERAPY [J].
DELMONICO, FL ;
FULLER, TC ;
RUSSELL, PS ;
COLVIN, RB ;
COSIMI, AB .
TRANSPLANTATION, 1989, 47 (01) :92-95
[9]   NONHUMAN PRIMATE RESPONSES TO MURINE AND HUMANIZED OKT4A [J].
DELMONICO, FL ;
COSIMI, AB ;
KAWAI, T ;
CAVENDER, D ;
LEE, WH ;
JOLLIFFE, LK ;
KNOWLES, RW ;
SCHROEDER ;
KAHAN .
TRANSPLANTATION, 1993, 55 (04) :722-728
[10]   STRUCTURE OF DOMAIN-1 OF RAT LYMPHOCYTE-T CD2 ANTIGEN [J].
DRISCOLL, PC ;
CYSTER, JG ;
CAMPBELL, ID ;
WILLIAMS, AF .
NATURE, 1991, 353 (6346) :762-765