Summary
Murine monoclonal antibodies are used to abrogate immunological rejection of vascularised organ grafts in humans. The most widely-used antibody, muromonab CD3 (OKT3), has specificity for the human peripheral T cell antigen CD3. Systemic administration of muromonab CD3 in essential organ transplantation is associated with 2 major types of complications: infections and the so-called cytokine release syndrome. In addition, most recipients produce antibodies to the heterologous murine immunoglobulin. Muromonab CD3 has also been implicated in precipitating some ocular complications. Some of these adverse effects are likely to be attendant on the administration of any immunosuppressive murine monoclonal antibody, irrespective of specificity.
The use of monoclonal antibodies in corneal transplantation has thus far been limited, and has been restricted primarily to studies in experimental animals. Systemic administration of monoclonal antibodies with specificity for the T cell subset determinant CD4 has already been shown to prolong orthotopic corneal allograft and heterotopic corneal xenograft survival in small rodents. Further, the intracameral injection of anti-T cell monoclonal antibodies into the anterior chamber of the eye has been shown to reverse acute corneal graft rejection in humans, while antibodies with specificity for T cells and myeloid cells were similarly effective in a rabbit model. These studies clearly demonstrate that monoclonal antibodies can be used to both prevent and reverse corneal graft rejection.
The challenges are now 3-fold. First, the most appropriate specificity and route of administration of monoclonal antibodies for the immunosuppression of corneal grafts need to be determined. Secondly, it will be necessary to establish that these reagents can be given safely in the clinical setting without causing unacceptable adverse effects. Finally, it must be confirmed that monoclonal antibodies will prove to be useful adjuncts (or better alternatives) to existing regimens of immunosuppression for corneal transplantation.
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References
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 475–81
Williams KA, Muehlberg SM, Wing SJ, et al. The Australian Corneal Graft Registry, 1990-1992 report. Aust NZ J Ophthalmol 1993; 21(Suppl.): 1–48
Köhler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 1975; 256: 495–7
Cosimi AB, Burton RC, Colvin RB, et al. Treatment of acute renal allograft rejection with OKT3 monoclonal antibody. Transplantation 1981; 32: 535–9
Ortho Multicenter Transplant Study Group. A randomized clinical trial of OKT3 monoclonal antibody for acute rejection of cadaveric renal transplants. N Engl J Med 1985; 313: 337–42
Cosimi AB, Cho SI, Delmonico FL, et al. A randomized clinical trial comparing OKT3 and steroids for treatment of hepatic allograft rejection. Transplantation 1987; 43: 91–5
Colonna JO, Goldstein LI, Brems JJ, et al. A prospective study on the use of monoclonal anti-T3-cell antibody (OKT3) to treat steroid-resistant liver transplant rejection. Arch Surg 1987; 122: 1120–3
Gilbert EM, Dewitt CW, Eiswirth CC, et al. Treatment of refractory cardiac allograft rejection with OKT3 monoclonal antibody. Am J Med 1987; 82: 202–6
Cecka JM, Gjertson D, Terasaki PI. Do prophylactic antilymphocyte globulins (ALG and OKT3) improve renal transplant survival in recipient and donor high-risk groups? Transplant Proc 1993; 25: 548–9
Millis JM, McDiarmid SV, Hiatt JR, et al. Randomized prospective trial of OKT3 for early prophylaxis of rejection after liver transplantation. Transplantation 1989; 47: 82–8
Gilbert EM, Eiswirth CC, Renlund DG, et al. Use of Orthoclone OKT3 monoclonal antibody in cardiac transplantation: early experience with rejection prophylaxis and treatment of refractory rejection. Transplant Proc 1987; 19(1 Suppl.): 45–53
Oh CS, Stratta RJ, Fox BC, et al. Increased infections associated with the use of OKT3 for treatment of steroid-resistant rejection in renal transplantation. Transplantation 1988; 45: 68–73
Jeyarajah DR, Thistlethwaite JR. General aspects of cytokinerelease syndrome: timing and incidence of symptoms. Transplant Proc 1993; 25 (1 Suppl.): 16–20
Abramowicz D, Schandene L, Goldman M, et al. Release of tumor necrosis factor, interleukin-2, and gamma-interferon in serum after injection of OKT3 monoclonal antibody in kidney graft recipients. Transplantation 1989; 47: 606–8
Chatenoud L, Ferran C, Legendre C, et al. In vivo cell activation following OKT3 administration. Systemic cytokine release and modulation by corticosteroids. Transplantation 1990; 49: 697–702
Chatenoud L. OKT3-induced cytokine-release syndrome: preventive effect of anti-tumor necrosis factor monoclonal antibody. Transplant Proc 1993; 25 (1 Suppl.): 47–51
Jaffers GJ, Fuller TC, Cosimi AB, et al. Monoclonal antibody therapy: anti-idiotypic and non-anti-idiotypic antibodies to OKT3 arising despite intense immunosuppression. Transplantation 1986; 41: 572–8
Chatenoud L, Baudrihaye MF, Chkoff N, et al. Restriction of the human in vivo immune response against the mouse monoclonal antibody OKT3. J Immunol 1986; 137: 830–8
Chatenoud L. Humoral immune response against OKT3. Transplant Proc 1993; 25(1 Suppl.): 68–73
Chatenoud L, Bach J-F. Therapeutic monoclonal antibodies in transplantation. Transplant Proc 1993; 25: 473–4
McCarthy JM, Sullivan K, Keown PA, et al. Diffuse anterior scleritis during monoclonal antibody therapy for renal transplant rejection. Can J Ophthalmol 1992; 27: 22–4
Dukar O, Barr CC. Visual loss complicating OKT3 monoclonal antibody therapy. Am J Ophthalmol 1993; 115: 781–5
Shihab FS, Barry JM, Norman DJ. Encephalopathy following the use of OKT3 in renal allograft rejection. Transplant Proc 1993; 25(1 Suppl.): 31–4
Norman DJ, Chatenoud L, Cohen D, et al. Consensus statement regarding OKT3-induced cytokine-release syndrome and human antimouse antibodies. Transplant Proc 1993; 25(1 Suppl.): 89–92
Dantal J, Soulillou J-P. Use of monoclonal antibodies in human transplantation. Curr Opin Immunol 1991; 3: 740–7
Ito T, Miyasaka M, Nozawa M. Monoclonal antibodies to adhesion molecules: therapeutic use in transplant rejection. Clin Immunother 1994; 1: 460–8
Norman DJ, Bennett WM, Cobanoglu A, et al. Use of OKT4A (a murine monoclonal anti-CD4 antibody) in human organ transplantation: initial clinical experience. Transplant Proc 1993; 25: 802–3
Reiter CH, Meiser BM, Uberfuhr P, et al. Selection and chimerization of a monoclonal CD4 antibody for heart transplantation. Transplant Proc 1993; 25: 788–9
Le Mauff B, Hourmant M, Rougier J-P, et al. Effect of anti-LFA1 (CD 11 a) monoclonal antibodies in acute rejection in human kidney transplantation. Transplantation 1991; 52: 291–6
Haug CE, Colvin RB, Delmonoco FL, et al. A phase I trial of immunosuppression with anti-ICAM-1 (CD54) mAb in renal allograft recipients. Transplantation 1993; 55: 766–73
Soulillou J-P, Cartovarich D, Le Mauff B, et al. Randomized trial of an anti-interleukin 2 receptor monoclonal antibody (33B3.1) versus rabbit antithymocyte globulin (ATG) in prophylaxis of early rejection in human renal transplantation. N Engl J Med 1990; 322: 1175–82
Kriaa F, Hiesse C, Alard P, et al. Prophylactic use of the anti-IL-2 receptor monoclonal antibody LO-Tact-1 in cadaveric renal transplantation: results of a randomized study. Transplant Proc 1993; 25: 817–9
Herbert J, Roser B. Strategies of monoclonal antibody therapy that induce permanent tolerance of organ transplants. Transplantation 1988; 46(Suppl.): 128–34
Sablinski T, Hancock WH, Tilney NL, et al. CD4 monoclonal antibodies in organ transplantation - a review of progress. Transplantation 1991; 52: 579–89
Waldmann H. Immunosuppression with monoclonal antibodies: some speculations about tolerance in the context of tissue grafting. Transplant Proc 1988; 20 (8 Suppl.): 46–52
Waltman SR, Faulkner WM, Burde RM. Modification of the ocular immune response. I. Use of antilymphocytic serum to prevent immune rejection of penetrating corneal homografts. Invest Ophthalmol 1972; 8: 196–200
Polack FM, Townsend WM, Waltman S. Antilymphocyte serum and corneal graft rejection. Am J Ophthalmol 1972; 73: 52–5
Smolin G. Corneal homograft reaction following subconjunctival antilymphocyte serum. Am J Ophthalmol 1969; 67: 137–9
Ayliffe W, Alam Y, Bell EB, et al. Prolongation of rat corneal graft survival by treatment with anti-CD4 monoclonal antibody. Br J Ophthalmol 1992; 76: 602–6
He YG, Ross J, Niederkorn JY. Promotion of murine orthotopic corneal allograft survival by systemic administration of anti-CD4 monoclonal antibody. Invest Ophthalmol Vis Sci 1991; 32: 2723–8
Duguid IGM, Koulmanda M, Mandel TE. Prolongation of heterotopic human corneal graft survival in mice treated with an anti-CD4 monoclonal antibody. Transplant Proc 1990; 22: 2107–8
Guymer RH, Mandel TE. Monoclonal antibody to ICAM-1 prolongs murine heterotopic corneal allograft survival. Aust NZ J Ophthalmol 1991; 19: 141–4
Shirao E, Deschênes J, Char DH. Corneal allograft rejection in rabbits. Curr Eye Res 1986; 5: 817–22
Williams KA, Standfield SD, Wing SJ, et al. Patterns of corneal graft rejection in the rabbit and reversal of rejection with monoclonal antibodies. Transplantation 1992; 54: 38–43
Williams KA, Coster DJ. Local injection of monoclonal antibodies into the anterior chamber of rabbits with corneal graft rejection. In: Usui M, Ohno S, Aoki K, editors. Ocular immunology today. Amsterdam: Elsevier, 1990: 107–10
Ippoliti G, Fronterrè A. Use of locally injected anti-T monoclonal antibodies in the treatment of acute corneal graft rejection. Transplant Proc 1987; 19: 2579–80
Ippoliti G, Fronterrè A. Usefulness of CD3 or CD6 anti-T monoclonal antibodies in the treatment of acute corneal graft rejection. Transplant Proc 1989; 21: 3133–4
Council on Scientific Affairs. Report of the organ transplant panel: corneal transplantation. JAMA 1988; 259: 719–22
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This work was supported by the Ophthalmic Research Institute of Australia and the National Health and Medical Research Council. We thank E.W. Johnstone for the artwork.
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Williams, K.A., Coster, D.J. Use of Monoclonal Antibodies in Corneal Transplantation. Clin Immunother 2, 32–41 (1994). https://doi.org/10.1007/BF03258520
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DOI: https://doi.org/10.1007/BF03258520