Effective use of donor MHC class I gene therapy in organ transplantation: Prevention of antibody-mediated hyperacute heart allograft rejection in highly sensitized rat recipients

被引:16
作者
Geissler, EK
Graeb, C
Tange, S
Guba, M
Jauch, KW
Scherer, MN
机构
[1] Univ S Alabama, Dept Clin Lab Sci, Mobile, AL 36604 USA
[2] Univ Regensburg, Dept Surg, D-93053 Regensburg, Germany
关键词
D O I
10.1089/10430340050015923
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Immunologically sensitized recipients present one of the most critical problems in clinical organ transplantation today, since preformed antibodies rapidly destroy donor tissue expressing specific MHC class I antigens (Ag), Therefore, sensitized patients are either unable to receive a compatible organ, or experience a prolonged waiting period. In this study we examined the effectiveness of donor MHC class I gene therapy in preventing hyperacute rejection (HR) of rat heart allografts in passively sensitized recipients. Our gene therapy strategy to address this problem is based on the phenomenon that liver transplants, which resist antibody-mediated HR, produce soluble MHC class I Ag capable of neutralizing:preformed antibodies and suppressing the immune response. To mimic this "liver effect," we used liposomes to transfect cultured recipient (Lewis-RT1.A(1)) hepatocytes with plasmid DNA encoding the soluble: donor MHC class I Ag, RT1.A(a), Control or RT1.A(a)-transfected hepatocytes were implanted intrasplenically into Lewis recipients 1 day prior to heterotopic ACI (RT1.A(a)) heart transplantation and injection of 6 ml of anti-ACI hyperimmune serum (HIS), Results showed that nearly all recipients receiving ACI-specific HIS and control hepatocytes experienced HR, while none of the recipients receiving HIS and hepatocytes expressing soluble RT1.A(a) developed HR, Furthermore, active immunosuppression by soluble RT1.A(a) was evidenced by prolongation of allograft survival, compared with controls not receiving HIS. In summary, soluble donor-MHC class I Ag gene therapy can prevent antibody-mediated destruction associated with HR, Future development of a similar strategy in humans may significantly improve the results of clinical organ transplantation in immunologically sensitized recipients.
引用
收藏
页码:459 / 469
页数:11
相关论文
共 43 条
[21]   PERMANENT ENGRAFTMENT AND FUNCTION OF HEPATOCYTES DELIVERED TO THE LIVER - IMPLICATIONS FOR GENE-THERAPY AND LIVER REPOPULATION [J].
GUPTA, S ;
ARAGONA, E ;
VEMURU, RP ;
BHARGAVA, KK ;
BURK, RD ;
CHOWDHURY, JR .
HEPATOLOGY, 1991, 14 (01) :144-149
[22]   THE IMMUNE-COMPLEX - POSSIBLE WAYS OF REGULATING THE ANTIBODY-RESPONSE [J].
HEYMAN, B .
IMMUNOLOGY TODAY, 1990, 11 (09) :310-313
[23]   IMMUNOADSORPTION OF ANTI-HLA ANTIBODIES FOR HIGHLY SENSITIZED PATIENTS AWAITING RENAL-TRANSPLANTATION [J].
HIESSE, C ;
KRIAA, F ;
ROUSSEAU, P ;
FARAHMAND, H ;
BISMUTH, A ;
FRIES, D ;
CHARPENTIER, B .
NEPHROLOGY DIALYSIS TRANSPLANTATION, 1992, 7 (09) :944-951
[24]  
KAMEI T, 1990, SURGERY, V108, P415
[25]  
KOKUDO N, 1995, TRANSPLANTATION, V60, P200
[26]   Hepatocyte gene therapy in a large animal: A neonatal bovine model of citrullinemia [J].
Lee, B ;
Dennis, JA ;
Healy, PJ ;
Mull, B ;
Pastore, L ;
Yu, H ;
Aguilar-Cordova, E ;
O'Brien, W ;
Reeds, P ;
Beaudet, AL .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (07) :3981-3986
[27]   NUCLEOTIDE-SEQUENCE OF RAT BETA-2-MICROGLOBULIN CDNA [J].
MAUXION, F ;
KRESS, M .
NUCLEIC ACIDS RESEARCH, 1987, 15 (18) :7638-7638
[28]   PRIMARY CULTURE OF PARENCHYMAL LIVER-CELLS ON COLLAGEN MEMBRANES - MORPHOLOGICAL AND BIOCHEMICAL OBSERVATIONS [J].
MICHALOPOULOS, G ;
PITOT, HC .
EXPERIMENTAL CELL RESEARCH, 1975, 94 (01) :70-78
[29]   EARLY INTERACTIONS OF CANCER-CELLS WITH THE MICROVASCULATURE IN MOUSE-LIVER AND MUSCLE DURING HEMATOGENOUS METASTASIS - VIDEOMICROSCOPIC ANALYSIS [J].
MORRIS, VL ;
MACDONALD, IC ;
KOOP, S ;
SCHMIDT, EE ;
CHAMBERS, AF ;
GROOM, AC .
CLINICAL & EXPERIMENTAL METASTASIS, 1993, 11 (05) :377-390
[30]   ADVANTAGES OF DONOR-SPECIFIC BLOOD-TRANSFUSION IN THE RAT VIA THE PORTAL-VEIN FOR RENAL-TRANSPLANTATION [J].
NAKAFUSA, Y ;
TERASAKA, R ;
MATSUO, K ;
KONOMI, K ;
FLYE, MW .
AMERICAN JOURNAL OF KIDNEY DISEASES, 1993, 21 (04) :433-438