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J Thorac Cardiovasc Surg 1997;113:417-419
© 1997 Mosby, Inc.

BRIEF COMMUNICATIONS

HLA ANTIBODIES SPECIFIC FOR CRYOPRESERVED HEART VALVE "HOMOGRAFTS'" IN CHILDREN

Groningen, The Netherlands

Received for publication March 22, 1996 accepted for publication May 3, 1996. Address for reprints: Jochum Prop, MD, Cardiopulmonary Surgery, Research Division, University Hospital Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands.

For more than 30 years, human heart valves have been used as grafts for replacement of diseased aortic and pulmonary valves. These heart valve allografts, traditionally referred to as "homografts,'" were long assumed to be immunologically inert and were supposed not to be affected by rejection, in contrast to organ transplants. However, in children, degeneration of the heart valve allografts is frequently observed. ¹ Findings in clinical ^2,3 and experimental ⁴ studies suggested that this degeneration might be caused by an immune response. Recently, Smith and colleagues ⁵ from the Harefield Hospital, United Kingdom, found donor HLA–specific antibodies in adults after implantation of fresh or antibiotic-sterilized aortic valve allografts. This demonstrated that human heart valve allografts can induce immune responses in patients.

Most cardiac centers do not have fresh heart valve allografts available and use cryopreserved valves instead, which have been shown to become less immunogenic during the cryopreservation procedure. ³ Therefore we investigated whether cryopreserved heart valve allografts induced donor-specific HLA antibodies in children.

Eight children who underwent operation for congenital heart defects (Table I) were studied between 2 weeks and 5 years after implantation of a cryopreserved heart valve allograft. The age of the children at the time of operation ranged from 1 month to 17 years; two of the children had undergone operation twice; all but one of the children received unfiltered red blood cell concentrates (Table I). In a study protocol approved by the Medical Ethical Committee of our institution, the patients (and parents) allowed collection of a single blood sample for analysis of HLA antibodies; no permission was obtained for HLA typing in these patients.

Cytotoxic HLA antibodies were detected in the serum of four of the eight children. In three children HLA antibodies of the IgG isotype were directed specifically against HLA antigens of the allograft donor; the donor specificity of the IgM HLA antibodies detected in the fourth patient could not be confirmed because the donor HLA typing was not available.

In one patient, with HLA antibodies specific for the relatively rare HLA-B5 and -B49 antigens, analysis was done in detail, to exclude the possibility that the HLA antibodies were induced by blood transfusions. All but one of the blood donors were retrospectively typed for HLA antigens. None of the blood donors had the B5 or B49 antigens (Table II) and the crossmatches between the serum of the patient and lymphocytes of the blood donors were all negative. One blood donor was not available for HLA typing but it is unlikely that this single donor had HLA antigens corresponding with the specificities of the HLA antibodies.

Another way to prevent immune responses against valve allografts is prospective selection of an HLA-matched valve for each patient. Ideally the allografts should be matched for both HLA class I and II antigens. Class I matching has been shown to reduce rejection in high-risk corneal transplantation ⁸ and class II matching reduced in vitro the stimulation of lymphocytes by heart valve tissue. ³ The major obstacle to achieving adequate HLA matching of heart valve allografts, next to size matching, is that it would restrict the availability of suitable valve allografts for individual patients. In addition, the effect of prospective matching would only be of benefit for patients with an increased risk for degeneration of the valves. At present it is impossible to assess prospectively which patients are at risk for immune-mediated valve degeneration. However, children listed for retransplantation for reasons other than technical failure and children with preformed HLA antibodies are likely candidates. We recommend that for these patients at "high risk'" a crossmatch-negative, HLA-matched heart valve allograft be selected.

Acknowledgments

The cooperation of the Stichting Rode Kruis Bloedbank Noord Nederland, their blood donors, and Bio Implant Services for providing the HLA types of the donors is gratefully acknowledged.

Footnotes

From the Departments of Cardiopulmonary Surgery,^a Transplantation Immunology,^b and Pediatric Cardiology,^c University Hospital Groningen, Groningen, The Netherlands.

References

1. Clarke DR, Campbell DN, Hayward AR, Bishop DA. Degeneration of aortic valve allografts in young recipients. J Thorac Cardiovasc Surg 1993;105:934-42.[Abstract]
   
2. Yankah AC, Wottge HU, Muller-Hermelink HK, et al. Transplantation of aortic and pulmonary allografts, enhanced viability of endothelial cells by cryopreservation, importance of histocompatibility. J Card Surg 1987;2(suppl):209-20.[Medline]
   
3. Hoekstra F, Knoop C, Jutte N, et al. Effect of cryopreservation and HLA-DR matching on the cellular immunogenicity of human cardiac valve allografts. J Heart Lung Transplant 1994;13:1095-8.[Medline]
   
4. Zhao XM, Green M, Frazer IH, Hogan P, O'Brien MF. Donor-specific immune response after aortic valve allografting in the rat. Ann Thorac Surg 1994;57:1158-63.[Abstract]
   
5. Smith JD, Ogino H, Hunt D, Laylor RM, Rose ML, Yacoub MH. Humoral immune response to human aortic valve homografts. Ann Thorac Surg 1995;60:S127-30.
   
6. Scornic JC, Pfaff WW, Howard RJ, et al. Increased antibody responsiveness to blood transfusions in pediatric patients. Transplantation 1994;58:1361-5.[Medline]
   
7. Yankah AC, Wottge HU, Muller-Rucholtz W. Short-course cyclosporin a therapy for definite allograft valve survival immunosuppression in allograft valve operations. Ann Thorac Surg 1995;60:146-50.
   
8. Sanfilippo F, MacQueen JM, Vaughn WK, Foulks GN. Reduced graft rejection with good HLA-A and B matching in high-risk corneal transplantation. N Engl J Med 1986;315:29-35.[Abstract]
   

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