Agonistic Autoantibodies and Rejection of Renal Allografts
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《新英格兰医药杂志》
Allograft rejection remains a major problem in renal transplantation, despite the substantial improvements in post-transplantation management that now result in fewer acute rejection episodes and better overall survival.1 Rejection can be an acute event or a chronic, indolent process in which fibrosis within the graft is prominent and ultimately results in graft loss. Allograft rejection is usually considered to be mediated by T cells, but there is substantial evidence of antibody-mediated injury to the graft outside the now rare context of hyperacute rejection (which occurs when high titers of anti-HLA antibodies are present before transplantation2). Indeed, antibody-mediated rejection (also called humoral or vascular rejection) is currently thought to play a role in about one third of acute rejection episodes.3 Acute humoral rejection is generally resistant to treatment, ending far too frequently with the devastating loss of a transplanted kidney.
The serum of many, if not most, patients in whom acute antibody-mediated rejection develops contains antibodies against HLA antigens.2,3 These antibodies have long been considered to be the factor that initiates acute rejection. Some affected transplant recipients have had one or more previous allografts, have an incompatible crossmatch with the HLA antigens of a prospective donor, or have antibodies against a panel of HLA antigens. Antibodies against HLA antigens can be induced in pregnant women by paternal antigens expressed by the fetus. These antibodies can persist for years, even without further pregnancies. There are, however, many cases in which the putative pathogenic antibodies are directed not against the HLA or ABO system, but against other cellular targets. Some patients in this latter category have also received previous allografts or have been pregnant in the past. Patients with rejection mediated by non-HLA antibodies are particularly difficult to treat and frequently lose their grafts. For this reason, it is important to identify and elucidate the mechanisms by which non-HLA antibodies contribute to humoral rejection.
Biopsy of the transplant is the standard method of diagnosing humoral rejection, and advances in techniques by which biopsy specimens can be studied have led to a better understanding of humoral rejection. Antibody-mediated rejection targets antigens on the endothelium, classically the class I and class II HLA antigens and AB blood-group antigens.3 When bound to their respective antigens, these antibodies activate the complement system. When C3 and C4 are generated, their products, C3d and, particularly, C4d, bind covalently to vessel walls.3 Indeed, the presence of C4d in vessels of the graft is a good marker of humoral rejection,3 though it is not entirely specific for this process.4 There are three types of antibody-mediated rejection: a subtle process, seen early, with edema, little inflammation, some tubular injury, and deposition of immunoglobulin and C4d in capillaries; capillaritis and glomerulitis with immunoglobulin and C4d in capillaries; and arteritis with deposits of immunoglobulin and C4d.3
Endothelial inflammation and subsequent cellular infiltration and endothelial disruption are hallmarks of antibody-mediated rejection in renal allografts.5 Activation or apoptosis of endothelial cells, or both, also occurs, suggesting that non-HLA antibodies may initiate a cascade of events that lead to vascular endothelial and tissue damage that might be averted by focusing therapy on either these antibodies or their targets.
In this issue of the Journal, Dragun et al.6 report the presence of agonistic antibodies against the angiotensin II type 1 (AT1) receptor in recipients of renal allografts who had severe vascular rejection and malignant hypertension and who did not have anti-HLA antibodies. These investigators studied 33 transplant recipients with refractory vascular rejection. Thirteen of these patients had donor-specific anti-HLA antibodies and deposits of C4d on kidney biopsy, whereas 20 had no detectable donor-specific anti-HLA antibodies. Sixteen of these 20 patients had malignant hypertension, and all 16 had circulating agonistic antibodies that targeted the AT1 receptor. C4d was detected in biopsy specimens from only 5 of these 16 patients, suggesting that the pathogenesis of rejection in patients with agonistic autoantibodies is distinct from that in patients with anti-HLA antibodies. Dragun and her coworkers also carried out experiments in which transfer of the agonistic antibodies into rats with kidney transplants induced vasculopathy and hypertension; in contrast, control rats that had undergone uninephrectomy of a native kidney were unaffected, supporting the concept that these antibodies are pathogenic and not an epiphenomenon.
Seven of the 16 patients with agonistic autoantibodies were treated with a combination of plasmapheresis, intravenous immune globulin infusion, and the AT1-receptor blocker losartan. This combination treatment led to improved renal function and graft survival, as compared with the outcomes among patients with agonistic autoantibodies who received standard treatment for humoral rejection. These preliminary observations suggest that preventing the agonistic antibodies from binding to their target receptors might prove a valuable treatment.
Although the role of agonistic antibodies in the pathogenesis of humoral rejection remains to be determined, agonistic antibodies have been detected in other conditions in which receptors are activated, leading to disease.7,8,9,10,11,12,13 In Graves' disease, agonistic antithyrotropin autoantibodies activate the thyrotropin receptor, increasing thyroxine production.7 Similarly, agonistic AT1-receptor antibodies have been associated with severe hypertension in preeclampsia,8,9 as well as in malignant hypertension.10 These autoantibodies generally bind to their targeted receptor, activating rather than inhibiting it. The decision to seek and isolate such antibodies in transplant recipients with humoral rejection was sparked by the observation that one of the patients in the present study had had preeclampsia many years before transplantation and the subsequent occurrence of humoral rejection.
The autoantibodies against the AT1 receptor appear to recognize a structure formed by the second extracellular loop of the receptor (Figure 1); this is similar to findings in patients with preeclampsia who had agonistic autoantibodies.9 The AT1 receptor, a G protein–coupled receptor with seven transmembrane domains, is responsible for most of the physiological cardiovascular effects mediated by angiotensin II. In cases of preeclampsia with agonistic AT1-receptor autoantibodies, angiotensin II binds to the AT1 receptor, causing activation of the phosphatidylinositol–calcium second-messenger system. Additional studies have demonstrated that monocytes can be stimulated by agonistic AT1 autoantibodies and angiotensin II to adhere to vascular endothelium and to produce tissue factor and possibly reactive oxygen species.14
Figure 1. Binding of Agonistic Antibodies to the AT1 Receptor.
Antibodies that target the AT1 receptor appear to bind to the receptor's second extracellular loop. Red indicates residues conserved among species. The line with the two S's denotes a disulfide bond. Adapted from Dechend et al.,9 with the permission of the publisher.
Two strategies for the treatment of vascular rejection are promising — removal of the antibodies, either by plasmapheresis or by absorption on an antigen-coated column, and use of a drug that competes with the antibodies for receptor binding. Thway et al.15 demonstrated that agonistic anti–AT1-receptor antibodies increase intracellular Ca2+ mobilization and that both the AT1-receptor antagonist losartan and a heptapeptide corresponding to a segment of the second extracellular loop of the AT1 receptor can attenuate this effect.
Why agonistic autoantibodies against the AT1 receptor develop in certain transplant recipients is not known. The answer may be helpful in the development of new therapies. Given what we do know, would preemptive treatment with AT1-receptor blockers in patients at risk for vascular rejection be successful? The authors suggest that such a strategy be considered but also acknowledge the long-held concern among transplantation physicians that drugs that interrupt the renin–angiotensin system might be particularly risky in transplant recipients, who have only a single functioning kidney. The observation that some of the patients in the present study appeared to benefit from the use of AT1-receptor blockers should provide the impetus for further study.
References
Halloran P. Immunosuppressive drugs for kidney transplantation. N Engl J Med 2004;351:2715-2729.
Ahern AT, Artruc SB, Della Pelle P, et al. Hyperacute rejection of HLA A-B identical renal allografts associated with B lymphocytes and endothelial reactive antibodies. Transplantation 1982;33:103-106.
Racusen LC. Antibody-mediated rejection in the kidney. Transplant Proc 2004;36:768-769.
Nickeleit V, Mihatsch MJ. Kidney transplants, antibodies and rejection: is C4d a magic marker? Nephrol Dial Transplant 2003;18:2232-2239.
Le Bas-Bernardet S, Hourmant M, Coupel S, Bignon JD, Soulillou JP, Charreau B. Non-HLA-type endothelial cell reactive alloantibodies in pre-transplant sera of kidney recipients trigger apoptosis. Am J Transplant 2003;3:167-177.
Dragun D, Müller DN, Br?sen JH, et al. Angiotensin II type 1-receptor-activating antibodies in renal-allograft rejection. N Engl J Med 2005;352:558-569.
Adams DD. Thyroid-stimulating autoantibodies. Vitam Horm 1980;38:119-203.
Wallukat G, Homuth V, Fischer T, et al. Patients with preeclampsia develop agonisitic autoantibodies against the angiotensin AT1 receptor. J Clin Invest 1999;103:945-952.
Dechend R, Muller DN, Wallukat G, et al. AT1 receptor agonistic antibodies, hypertension and preeclampsia. Semin Nephrol 2004;24:571-579.
Fu ML, Herlitz H, Schulze W, et al. Autoantibodies against the angiotensin receptor (AT1) in patients with hypertension. J Hypertens 2000;18:945-953.
Wallukat G, Wollenberger A, Morwinski R, Pitschner HF. Anti- 1-adrenoreceptor autoantibodies with chronotropic activity from the serum of patients with dilated cardiomyopathy: mapping of epitopes in the first and second extracellular loops. J Mol Cell Cardiol 1995;27:397-406.
Mijares A, Lebesgue D, Wallukat G, Hoebeke J. From agonist to antagonist: Fab fragments of an agonist-like monoclonal anti-(2)-adrenoceptor antibody behave as antagonists. Mol Pharmacol 2000;58:373-379.
Fu ML, Herlitz H, Wallukat G, et al. Functional autoimmune epitope on 1-adrenergic receptors in patients with malignant hypertension. Lancet 1994;344:1660-1663.
Dorffel Y, Wallukat G, Bochnig N, et al. Agonistic AT(1) receptor autoantibodies and monocyte stimulation in hypertensive patients. Am J Hypertens 2003;16:827-833.
Thway TM, Shlykov SG, Day MC, et al. Antibodies from pre-eclamptic patients stimulate increased intracellular Ca2+ mobilization through angiotensin receptor activation. Circulation 2004;110:1612-1619.(Julie R. Ingelfinger, M.D)
The serum of many, if not most, patients in whom acute antibody-mediated rejection develops contains antibodies against HLA antigens.2,3 These antibodies have long been considered to be the factor that initiates acute rejection. Some affected transplant recipients have had one or more previous allografts, have an incompatible crossmatch with the HLA antigens of a prospective donor, or have antibodies against a panel of HLA antigens. Antibodies against HLA antigens can be induced in pregnant women by paternal antigens expressed by the fetus. These antibodies can persist for years, even without further pregnancies. There are, however, many cases in which the putative pathogenic antibodies are directed not against the HLA or ABO system, but against other cellular targets. Some patients in this latter category have also received previous allografts or have been pregnant in the past. Patients with rejection mediated by non-HLA antibodies are particularly difficult to treat and frequently lose their grafts. For this reason, it is important to identify and elucidate the mechanisms by which non-HLA antibodies contribute to humoral rejection.
Biopsy of the transplant is the standard method of diagnosing humoral rejection, and advances in techniques by which biopsy specimens can be studied have led to a better understanding of humoral rejection. Antibody-mediated rejection targets antigens on the endothelium, classically the class I and class II HLA antigens and AB blood-group antigens.3 When bound to their respective antigens, these antibodies activate the complement system. When C3 and C4 are generated, their products, C3d and, particularly, C4d, bind covalently to vessel walls.3 Indeed, the presence of C4d in vessels of the graft is a good marker of humoral rejection,3 though it is not entirely specific for this process.4 There are three types of antibody-mediated rejection: a subtle process, seen early, with edema, little inflammation, some tubular injury, and deposition of immunoglobulin and C4d in capillaries; capillaritis and glomerulitis with immunoglobulin and C4d in capillaries; and arteritis with deposits of immunoglobulin and C4d.3
Endothelial inflammation and subsequent cellular infiltration and endothelial disruption are hallmarks of antibody-mediated rejection in renal allografts.5 Activation or apoptosis of endothelial cells, or both, also occurs, suggesting that non-HLA antibodies may initiate a cascade of events that lead to vascular endothelial and tissue damage that might be averted by focusing therapy on either these antibodies or their targets.
In this issue of the Journal, Dragun et al.6 report the presence of agonistic antibodies against the angiotensin II type 1 (AT1) receptor in recipients of renal allografts who had severe vascular rejection and malignant hypertension and who did not have anti-HLA antibodies. These investigators studied 33 transplant recipients with refractory vascular rejection. Thirteen of these patients had donor-specific anti-HLA antibodies and deposits of C4d on kidney biopsy, whereas 20 had no detectable donor-specific anti-HLA antibodies. Sixteen of these 20 patients had malignant hypertension, and all 16 had circulating agonistic antibodies that targeted the AT1 receptor. C4d was detected in biopsy specimens from only 5 of these 16 patients, suggesting that the pathogenesis of rejection in patients with agonistic autoantibodies is distinct from that in patients with anti-HLA antibodies. Dragun and her coworkers also carried out experiments in which transfer of the agonistic antibodies into rats with kidney transplants induced vasculopathy and hypertension; in contrast, control rats that had undergone uninephrectomy of a native kidney were unaffected, supporting the concept that these antibodies are pathogenic and not an epiphenomenon.
Seven of the 16 patients with agonistic autoantibodies were treated with a combination of plasmapheresis, intravenous immune globulin infusion, and the AT1-receptor blocker losartan. This combination treatment led to improved renal function and graft survival, as compared with the outcomes among patients with agonistic autoantibodies who received standard treatment for humoral rejection. These preliminary observations suggest that preventing the agonistic antibodies from binding to their target receptors might prove a valuable treatment.
Although the role of agonistic antibodies in the pathogenesis of humoral rejection remains to be determined, agonistic antibodies have been detected in other conditions in which receptors are activated, leading to disease.7,8,9,10,11,12,13 In Graves' disease, agonistic antithyrotropin autoantibodies activate the thyrotropin receptor, increasing thyroxine production.7 Similarly, agonistic AT1-receptor antibodies have been associated with severe hypertension in preeclampsia,8,9 as well as in malignant hypertension.10 These autoantibodies generally bind to their targeted receptor, activating rather than inhibiting it. The decision to seek and isolate such antibodies in transplant recipients with humoral rejection was sparked by the observation that one of the patients in the present study had had preeclampsia many years before transplantation and the subsequent occurrence of humoral rejection.
The autoantibodies against the AT1 receptor appear to recognize a structure formed by the second extracellular loop of the receptor (Figure 1); this is similar to findings in patients with preeclampsia who had agonistic autoantibodies.9 The AT1 receptor, a G protein–coupled receptor with seven transmembrane domains, is responsible for most of the physiological cardiovascular effects mediated by angiotensin II. In cases of preeclampsia with agonistic AT1-receptor autoantibodies, angiotensin II binds to the AT1 receptor, causing activation of the phosphatidylinositol–calcium second-messenger system. Additional studies have demonstrated that monocytes can be stimulated by agonistic AT1 autoantibodies and angiotensin II to adhere to vascular endothelium and to produce tissue factor and possibly reactive oxygen species.14
Figure 1. Binding of Agonistic Antibodies to the AT1 Receptor.
Antibodies that target the AT1 receptor appear to bind to the receptor's second extracellular loop. Red indicates residues conserved among species. The line with the two S's denotes a disulfide bond. Adapted from Dechend et al.,9 with the permission of the publisher.
Two strategies for the treatment of vascular rejection are promising — removal of the antibodies, either by plasmapheresis or by absorption on an antigen-coated column, and use of a drug that competes with the antibodies for receptor binding. Thway et al.15 demonstrated that agonistic anti–AT1-receptor antibodies increase intracellular Ca2+ mobilization and that both the AT1-receptor antagonist losartan and a heptapeptide corresponding to a segment of the second extracellular loop of the AT1 receptor can attenuate this effect.
Why agonistic autoantibodies against the AT1 receptor develop in certain transplant recipients is not known. The answer may be helpful in the development of new therapies. Given what we do know, would preemptive treatment with AT1-receptor blockers in patients at risk for vascular rejection be successful? The authors suggest that such a strategy be considered but also acknowledge the long-held concern among transplantation physicians that drugs that interrupt the renin–angiotensin system might be particularly risky in transplant recipients, who have only a single functioning kidney. The observation that some of the patients in the present study appeared to benefit from the use of AT1-receptor blockers should provide the impetus for further study.
References
Halloran P. Immunosuppressive drugs for kidney transplantation. N Engl J Med 2004;351:2715-2729.
Ahern AT, Artruc SB, Della Pelle P, et al. Hyperacute rejection of HLA A-B identical renal allografts associated with B lymphocytes and endothelial reactive antibodies. Transplantation 1982;33:103-106.
Racusen LC. Antibody-mediated rejection in the kidney. Transplant Proc 2004;36:768-769.
Nickeleit V, Mihatsch MJ. Kidney transplants, antibodies and rejection: is C4d a magic marker? Nephrol Dial Transplant 2003;18:2232-2239.
Le Bas-Bernardet S, Hourmant M, Coupel S, Bignon JD, Soulillou JP, Charreau B. Non-HLA-type endothelial cell reactive alloantibodies in pre-transplant sera of kidney recipients trigger apoptosis. Am J Transplant 2003;3:167-177.
Dragun D, Müller DN, Br?sen JH, et al. Angiotensin II type 1-receptor-activating antibodies in renal-allograft rejection. N Engl J Med 2005;352:558-569.
Adams DD. Thyroid-stimulating autoantibodies. Vitam Horm 1980;38:119-203.
Wallukat G, Homuth V, Fischer T, et al. Patients with preeclampsia develop agonisitic autoantibodies against the angiotensin AT1 receptor. J Clin Invest 1999;103:945-952.
Dechend R, Muller DN, Wallukat G, et al. AT1 receptor agonistic antibodies, hypertension and preeclampsia. Semin Nephrol 2004;24:571-579.
Fu ML, Herlitz H, Schulze W, et al. Autoantibodies against the angiotensin receptor (AT1) in patients with hypertension. J Hypertens 2000;18:945-953.
Wallukat G, Wollenberger A, Morwinski R, Pitschner HF. Anti- 1-adrenoreceptor autoantibodies with chronotropic activity from the serum of patients with dilated cardiomyopathy: mapping of epitopes in the first and second extracellular loops. J Mol Cell Cardiol 1995;27:397-406.
Mijares A, Lebesgue D, Wallukat G, Hoebeke J. From agonist to antagonist: Fab fragments of an agonist-like monoclonal anti-(2)-adrenoceptor antibody behave as antagonists. Mol Pharmacol 2000;58:373-379.
Fu ML, Herlitz H, Wallukat G, et al. Functional autoimmune epitope on 1-adrenergic receptors in patients with malignant hypertension. Lancet 1994;344:1660-1663.
Dorffel Y, Wallukat G, Bochnig N, et al. Agonistic AT(1) receptor autoantibodies and monocyte stimulation in hypertensive patients. Am J Hypertens 2003;16:827-833.
Thway TM, Shlykov SG, Day MC, et al. Antibodies from pre-eclamptic patients stimulate increased intracellular Ca2+ mobilization through angiotensin receptor activation. Circulation 2004;110:1612-1619.(Julie R. Ingelfinger, M.D)