American Association of Endocrine Surgeons| Volume 128, ISSUE 6, P910-917, December 2000

Download started.


Overexpression of heme oxygenase-1 protects allogeneic thyroid grafts from rejection in naive mice


      Background. Endocrine allografts are an option for the treatment of endocrine failure. Methods. One lobe of the thyroid was transplanted under the kidney capsule. Results. C57BL/10 (H2b) thyroids were rejected in naive CBA (H2k) mice within 14 days after transplantation. When mice were treated with anti-CD4 monoclonal antibodies (mAb), all grafts survived for more than 60 days. The first grafts still survived after second C57BL/10 or Balb/c (H2d) thyroid grafts that were transplanted into the same recipients were rejected acutely, which suggests that the primary grafts were modified under anti-CD4 mAb treatment. To confirm this hypothesis, C57BL/10 thyroid grafts from anti-CD4 mAb-treated mice were retransplanted. All grafts survived in naive mice; this correlated with the overexpression of heme oxygenase-1 (HO-1) in the grafts. Next, an inhibitor of HO-1 (zinc protoporphyrin) or control compound (copper protoporphyrin) was injected intraperitoneally after transplantation of C57BL/10 thyroid grafts into the primary CBA recipients that had been treated with anti-CD4 mAb. The grafts in mice that had been treated with zinc protoporphyrin, but not copper protoporphyrin, were rejected when retransplanted to naive recipients. Conclusions. Overexpression of HO-1 correlated with the protection of fully allogeneic thyroid grafts from rejection when retransplanted into naive recipients. (Surgery 2000;128:910-7.)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Surgery
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Brinker KR
        • Dickerman RM
        • Gonwa TW
        • Hull AR
        • Langley JW
        • Long DY
        • et al.
        A randomized trial comparing double-drug and triple drug therapy in primary cadaveric renal transplants.
        Transplantation. 1990; 50: 43-49
        • London NJ
        • Farmery SM
        • Will EJ
        • Davison AM
        • Lodge JPA
        Risk of neoplasia in renal transplant patients.
        Lancet. 1995; 346: 403-406
        • Cobbold SP
        • Martin G
        • Qin S
        • Waldmann H
        Monoclonal antibodies to promote marrow engraftment and tissue graft tolerance.
        Nature. 1986; 323: 164-166
        • Niimi M
        • Hara M
        • Bushell A
        • Madsen JC
        • Morris PJ
        • Wood KJ
        Results of heart transplantation in mice.
        in: Organ transplantation in rats and mice. : Springer, Berlin1998: 637-647
        • Superina RA
        • Peugh WN
        • Wood KJ
        • Morris PJ
        Assessment of primarily vascularized cardiac allografts in mice.
        Transplantation. 1986; 42: 226-227
        • Madsen JC
        • Peugh WN
        • Wood KJ
        • Morris PJ
        The effect of anti-L3T4 monoclonal antibody treatment on first-set rejection of murine cardiac allografts.
        Transplantation. 1987; 44: 849-852
        • Swain SL
        T cell subsets and the recognition of MHC class.
        Immunol Rev. 1983; 74: 129-142
        • Cammarota G
        • Scheirle A
        • Takacs B
        • Doran DM
        • Knorr R
        • Bannwarth W
        • et al.
        Identification of a CD4 binding site on the *2 domain of HLA-DR molecules.
        Nature. 1992; 356: 799-801
        • Cobbold SP
        • Jayasuriya A
        • Nash A
        • Prospero TD
        • Waldmann H
        Therapy with monoclonal antibodies by elimination of T-cell subsets in vivo.
        Nature. 1984; 312: 548-551
        • Cosimi AB
        • Delmonico FL
        • Wright KJ
        • Wee SL
        • Preffer FI
        • Jolliffe LK
        • et al.
        Prolonged survival of nonhuman primate renal allograft recipients treated with only anti-CD4 monoclonal antibody.
        Surgery. 1990; 108: 406-413
        • Wood KJ
        • Pearson TC
        • Darby C
        • Morris PJ
        CD4: a potential target molecule for immunosuppressive therapy and tolerance induction.
        Transplant Rev. 1991; 5: 150-164
        • Shizuru JA
        • Gregory AK
        • Chao CTB
        • Fathman CG
        Islet allograft survival after a single course of treatment of recipients with antibody to L3T4.
        Science. 1987; 237: 278-280
        • Cobbold S
        • Waldmann H
        Skin allograft rejection by L3T4+ and LYT-2+ T cell subsets.
        Transplantation. 1986; 41: 634-639
        • Waldmann H
        Manipulation of T-cell responses with monoclonal antibodies.
        Annu Rev Immunol. 1989; 7: 407-444
        • Darby CR
        • Morris PJ
        • Wood KJ
        Evidence that long-term cardiac allograft survival induced by anti-CD4 monoclonal anti-body does not require depletion of CD4 + T cells.
        Transplantation. 1992; 54: 483-490
        • Bach FH
        • Ferran C
        • Hechenleitner P
        • Mark W
        • Koyamada N
        • Miyatake T
        • et al.
        Accommodation of vascularized xenografts: Expression of “protective gene” by donor endothelial cells in a host T H2 cytokine environment.
        Nature Med. 1997; 3: 196-204
        • Soares MP
        • Lin Y
        • Anrather J
        • Csizmadia E
        • Takigami K
        • Sato K
        • et al.
        Expression of heme oxygenase-1 can determine cardiac xenograft survival.
        Nat Med. 1998; 4: 1073-1077
        • Badrichani AZ
        • Stroka DM
        • Bilbao G
        • Curiel DT
        • Bach FH
        • Ferran C
        Bcl-2 and Bcl-XL serve an anti-inflammatory function in endothelial cells through inhibition of NF-kappaB.
        J Clin Invest. 1999; 103: 543-553
        • Grey ST
        • Arvelo MB
        • Hasenkamp W
        • Bach FH
        • Ferran C
        A20 inhibits cytokine-induced apoptosis and nuclear factor kappaB-dependent gene activation in islets.
        J Exp Med. 1999; 190: 1135-1146
        • Suematsu M
        • Ishimura Y
        The heme oxygenase-carbon monoxide system: a regulator of hepatobiliary function.
        Hepatology. 2000; 31: 3-6
        • Woo J
        • Iyer S
        • Cornejo MC
        • Mori N
        • Gao L
        • Sipos I
        • et al.
        Stress protein-induced immunosuppression: inhibition of cellular immune effector functions following overexpression of haem oxygenase (HSP 32).
        Transpl Immunol. 1998; 6: 84-93
        • Hancock WW
        • Buelow R
        • Sayegh MH
        • Turka LA
        Antibody-induced transplant arteriosclerosis is prevented by graft expression of anti-oxidant and anti-apoptotic genes.
        Nat Med. 1998; 4: 1392-1396
        • DeBruyne LA
        • Magee JC
        • Buelow R
        • Bromberg JS
        Gene transfer of immunomodulatory peptides correlates with heme oxygenase-1 induction and enhanced allograft survival.
        Transplantation. 2000; 69: 120-128
        • Keyse SM
        • Applegate LA
        • Tromvoukis Y
        • Tyrrell RM
        Oxidant stress leads to transcriptional activation of the human heme oxygenase gene in cultured skin fibroblasts.
        Mol Cell Biol. 1990; 10: 4967-4969
        • Applegate LA
        • Luscher P
        • Tyrrell RM
        Induction of heme oxygenase: a general response to oxidant stress in cultured mammalian cells.
        Cancer Res. 1991; 51: 974-978