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J Thorac Cardiovasc Surg 2003;126:247-252
© 2003 The American Association for Thoracic Surgery

Surgery for congenital heart disease

Immunogenicity of decellularized cryopreserved allografts in pediatric cardiac surgery: comparison with standard cryopreserved allografts

^a Department of Pediatric Cardiothoracic Surgery, Primary Children’s Medical Center and University of Utah, Salt Lake City, Utah, USA
^b Department of Pediatric Cardiology, Primary Children’s Medical Center and University of Utah, Salt Lake City, Utah, USA
^c Histocompatibility and Immunogenetics Laboratory, University of Utah Hospital, Salt Lake City, Utah., USA

Read at the Eighty-second Annual Meeting of The American Association for Thoracic Surgery, Washington, DC, May 5-8, 2002.

Recieved for publication June 7, 2003 Received for publication August 1, 2002; revisions received September 16, 2002; accepted for publication October 10, 2002.

^* Address for reprints: John A. Hawkins, MD, Pediatric Cardiothoracic Surgery, Primary Children’s Medical Center, 100 N Medical Dr, Salt Lake City, UT 84113, USA
jhawkins{at}med.utah.edu

	Abstract

Top Abstract Patients and methods Results Discussion References

 
BACKGROUND: Recognition of the immunogenicity of standard cryopreserved allografts has led to the development of new decellularized allografts (CryoValve SG; CryoLife, Inc, Kennesaw, Ga). This preliminary study examined the HLA antibody response to these decellularized allografts and compared it with the response to standard allograft material.

METHODS: We prospectively measured the frequency of panel-reactive HLA class I (HLA-A, HLA-B, and HLA-C) and class II (HLA-DR/DQ) alloantibodies in 14 children (age 8.5 ± 7.9 years) receiving decellularized, cryopreserved allografts, including 6 undergoing allograft patch insertion and 8 with a valved pulmonary allograft. We compared them with 20 historical control subjects (age 1.7 ± 2.4 years) undergoing implantation of standard cryopreserved allografts, 8 with valves and 12 with allograft patch. All patients had panel-reactive antibody levels measured before and at 1, 3, and 12 months after the operation. HLA class I and class II panel-reactive antibody levels were determined with a sensitive flow cytometry technique.

RESULTS: We found panel-reactive antibody levels in decellularized allografts to be elevated slightly from preoperative levels for both class I and class II antibodies at 1, 3, and 12 months (P > .05). The panel-reactive antibody level for both class I and class II antibodies were significantly lower for decellularized allografts as compared to standard allografts. Functionally, the allografts were similar with decellularized valved grafts showing a peak echo-determined systolic gradient of 13 ± 15 mm Hg at 8 ± 2.6 months postoperatively as compared to a gradient of 24 ± 18 mm Hg measured 12 ± 6 months postoperatively in standard allografts (P = .11).

CONCLUSIONS: Decellularized grafts elicited significantly lower levels of class I and class II HLA antibody formation at 1, 3, and 12 months after implantation than did standard cryopreserved allografts. Early hemodynamic function of decellularized grafts was similar to that of standard cryopreserved allograft valves. Further experience is necessary to determine whether the reduced immunogenicity of decellularized allografts will truly allow tissue ingrowth and improved long-term durability in patients.

Cryopreserved human allograft material is extensively used in cardiac surgery to reconstruct a variety of congenital cardiac defects and abnormalities. Because of the widespread use of this cryopreserved allograft material, immunologic consequences of allograft implantation have been investigated, as illustrated by reports from several groups of the activation of anti-HLA antibodies.^1-3 A new decellularized cryopreserved allograft preparation has become available that theoretically will eliminate the immune response and, it is hoped, allow host cell ingrowth and better durability.⁴ Only limited experience and information with this new tissue has been available to date, and only with older patients.^5,6 Before the use of this human cryopreserved decellularized tissue can become widespread, the immunologic consequences and implications of this new tissue and valve preparation must be evaluated in children. Infants and children tend to have the greatest immunologic reaction to cryopreserved allograft material,⁷ with a shorter period of freedom from reintervention after valved allograft implantation than is seen in adult patients.^8,9 Thus infants and children may have the most to gain from the development of newer technologies that abolish immunogenicity and prolong durability.

This preliminary study was undertaken to examine the immunogenicity of these new cryopreserved allograft valves and nonvalved patch tissue grafts as related to the development of anti-HLA antibodies. In addition, we compared this new tissue with more traditional cryopreserved allografts in terms of both functional results and rate of calcification.

	Patients and methods

Top Abstract Patients and methods Results Discussion References

 
Patients
We prospectively enrolled 14 patients who received decellularized cryopreserved allograft material (CryoValve SG; CryoLife, Inc, Kennesaw, Ga) for reconstruction of congenital cardiac defects. Ages of the patients ranged from 22 days to 21 years (mean ± SD 8.5 ± 7.9 years). Diagnoses included truncus arteriosus in 2 patients, tetralogy of Fallot in 3 patients, aortic stenosis with pulmonary valve replacement for concomitant Ross procedure in 3 patients, pulmonary stenosis and insufficiency in 1 patient, supravalvular pulmonary stenosis in 2 patients, supravalvular aortic stenosis in 1 patient, pulmonary artery aneurysm with pulmonary valve insufficiency in 1 patient, and pulmonary atresia with intact ventricular septum in 1 patient. The procedures included insertion of a valved pulmonary allograft in 8 cases, pulmonary artery monocusp insertion in the right ventricular outflow tract in 2 cases, supravalvular pulmonary patch angioplasty in 3 cases, and allograft patch aortoplasty in 1 case. The types of allografts inserted included valved pulmonic allografts in 8 cases, pulmonary artery patch (nonvalved) allografts in 4 cases, and pulmonary artery monocusp patch allografts in 2 cases. Seven of the 14 patients had undergone previous cardiac surgery, all without allograft implantation.

Historical control subjects were used for comparison and consisted of 20 patients unselected from previous studies who had undergone implantation of standard cryopreserved allograft material with identical techniques and methods of HLA testing, including both class I and class II antibodies.^10,11 This standard group underwent implantation of 8 valved allografts, 7 allograft patches, and 5 monocusp pulmonary patches. Ages of patients ranged from 12 days to 7 years (mean ± SD 1.7 ± 2.2 years). Implantation techniques, study methods, and testing were identical for both decellularized and standard allograft groups, and no attempt was made to match ABO blood types in either group.

Allografts
All allografts in this study were obtained from CryoLife, Inc. Standard cryopreserved allograft material was considered to be allograft material that was harvested and cryopreserved according to previously published methods.^12,13 Decellularized cryopreserved allograft material (SynerGraft; CryoLife, Inc) is prepared by harvesting techniques similar to those used for standard allograft material but undergoes a decellularization process that first involves cell lysis in hypotonic sterile water solution. After that, the allograft tissue is equilibrated in buffer and is treated by enzymatic digestion of nucleic acids with a combined solution of ribonuclease and deoxyribonuclease. The allograft tissue then undergoes a multiday washout in isotonic neutral buffer to further reduce cellular staining when evaluated with hematoxylin and eosin staining of cryosectioned tissue.⁴ The processed decellularized valves are then cryopreserved according to a controlled rate freezing protocol.¹⁴ The resulting decellularized cryopreserved allografts have been shown to have approximately a 99% reduction in staining of endothelial and interstitial cellular elements, as well as marked reduction in staining for class I and class II histocompatibility antigens.⁵

Study methods
The study protocol was approved by the institutional review board at Primary Children’s Medical Center as well as the University of Utah Medical Center. Informed consent was obtained from the parents or guardian of each patient before entrance into the study. Blood was obtained for HLA panel-reactive antibody (PRA) screens and specificity determination at the following times: immediately before the operation and approximately 1, 3, and 12 months after implantation of the allograft material. As part of the protocol, all patients received only blood products that had undergone both irradiation and leukocyte filtering to remove allogeneic white blood cells that could sensitize the patients.¹⁵ All blood products were irradiated with cesium 137 at 30 Gy and were filtered with the use of Purecell leukocyte reduction filters (Pall Biomedical Products Co, East Hills, NY). Children with identified immunologic deficiencies such as DiGeorge syndrome were excluded from the study.

HLA-A, HLA-B, and HLA-C (class I) and HLA-DR/DQ (class II) antibodies were determined by a sensitive flow cytometry procedure.¹⁶ This technique uses affinity-purified, soluble class I and class II antigens from 30 different cell lines that are coupled individually to latex beads and then pooled together to create a panel that represents the majority of serologically recognized HLA class I and class II alloantigens (Flow-PRA I and II Beads; One Lambda, Canoga Park, Calif). The beads were incubated with 0.02 mL of patient serum and then washed washing and stained with saturating fluorescein-conjugated goat antihuman immunoglobulin G. After analysis on a Becton Dickinson FACScan flow cytometer (BD Immunocytometry Systems, San Jose, Calif), the percentage of fluorescent positive beads, indicative of the percentage of PRA, was calculated.

Patients with valved allografts in both groups underwent echocardiographic follow-up consisting of standard surface 2-dimensional and Doppler echocardiography. Allograft stenosis was evaluated with standard Doppler techniques. The peak velocity across the valved conduits was obtained with pulsed or continuous-wave Doppler evaluation, and the gradient was determined with the modified Bernoulli equation. Pulmonary valve regurgitation was graded echocardiographically according to a method described previously by us that has been validated and compared with traditionally used angiographic measures.¹⁷ According to this method, the ratio of the width of the pulmonary regurgitation color jet to the diameter of the valve annulus in early diastole is used as semiquantitative index of severity. A color jet to annulus ratio less than 0.4 is classified as mild (1+), a ratio of at least 0.4 but less than 0.7 is classified as moderate (2+), and a ratio of at least 0.7 is classified as severe (3+).

Statistical analysis
Comparisons between continuous data were made with unpaired t test or analysis of variance and Scheffé post hoc analysis. All data were expressed as mean ± SD.

	Results

Top Abstract Patients and methods Results Discussion References

 
Results are shown in Table 1. Both class I and class II HLA antibodies were elevated slightly from baseline values in patients receiving decellularized grafts at 1, 3, and 12 months, although these differences were not significant. However, all values beyond baseline preoperative time point for both class I and class II HLA antibodies were significantly less in decellularized allografts than their corresponding values at the same time period for standard allografts. Overall, 9 of the 14 patients exhibited no humoral response, as defined as an elevation of PRA greater than 10% for either class I or class II antibodies at any time period after the operation. Two other patients exhibited elevation of PRA greater than 10% for both class I and class II antibodies at 1 month, with 1 patient showing resolution of the PRA to less than 10% for class II antibodies by 1 year after the operation. Three additional patients showed elevation of PRA greater than 10% for just class II antibodies by 3 months after the operation, but by 1 year only 2 of these patients still had a PRA level greater than 10% for class II antibodies. Results for both class I and class II HLA antibodies in the standard allograft group are shown in Table 1 and have been previously reported.^10,11

View larger version (86K): [in this window] [in a new window]   Figure 1. Photomicrograph of decellularized cryopreserved pulmonary allograft explanted 4 months after operation. There is evidence of cellular ingrowth into media of graft, but no apparent cell staining of endothelial cells on luminal side of graft (bottom).

	Discussion

Top Abstract Patients and methods Results Discussion References

This study demonstrated in a prospective manner that these new decellularized allografts elicit a significantly reduced immune response to both class I (anti–HLA-A, anti–HLA-B, and anti–HLA-C) and class II (anti–HLA-HLA DR/DQ) alloantigens. Why a few patients respond immunologically (PRA 10%), even in a transient fashion, while most do not, cannot be yet be determined. The alloantibody elicited in these grafts toward HLA-DR antigens is intriguing and may suggest some residual cells, notably highly immunogenic, HLA class II–expressing dendritic cells that may be more resistant to the decellularization process.

Although it has not been definitely proved, we and others have speculated that the vigorous immune response measured by an elevated PRA may have significant negative effects on allograft function and longevity.^2,3,7,10,11 The advantages of reduced immunogenicity are thus 2-fold. First, an absent or at least reduced immunologic response will allow investigators to better sort out the role that immunology plays in allograft failure in children. Although immunologic factors are likely to play a role in allograft failure, they are intertwined with other factors associated with graft failure, such as patient age, graft size, donor age, and allograft type, making isolation of a single factor difficult. Second, the presence of both class I and class II HLA antibodies has significant implications if future heart or other organ transplantation is needed. Some children receiving allograft valves or allograft patch material have significant heart disease or undergo palliative procedures anticipated to result in late transplantation. Examples of a group of patients who are at risk for needing late transplantation include those with single-ventricle physiology undergoing palliative procedures with pulmonary artery reconstruction with allograft patches and children with hypoplastic left heart syndrome undergoing stage I palliation with a Norwood procedure. The presence of donor-specific HLA class I and class II antibodies has been shown to increase the risk of acute or hyperacute cardiac allograft rejection and to decrease graft survival.^23,24 In addition, extremely high and sustained PRA levels, as we^3,10,11 and others^19-22 have previously reported, may preclude or at least significantly delay transplantation until a crossmatch-compatible donor can be identified. Implantation of decellularized grafts, with the lower level of PRA and even the absence of a response in most cases, removes this impediment to transplantation.

There are several limitations of this study that make it harder to determine whether decellularized allografts are really an advance with respect to standard cryopreserved allografts. First, this study is limited by a duration of follow-up of less than 1 year and the relatively small number of patients followed up during that time. Deterioration of cryopreserved valved allografts is usually seen in the 3- to 5-year range for infants and the 5- to 10-year range for older children.^8,9 It will therefore take much larger numbers and longer follow-up to document definitive improvement in graft durability and function. Second, the comparison group in this study was a historical group rather than a randomized cohort. Although the methods used in the two study groups were identical, the ages of the two groups were different. There has been previous evidence of an increased immunologic response in infants relative to adults, but we have not seen any difference in PRA response in either class I or class II antibodies in infants as compared with older children in any of our previous studies.^{3,10,11,25,26} Use of a randomized group of larger numbers of patients would allow the most accurate comparison. In multiple other studies with standard cryopreserved allografts, however, we have never been able to demonstrate the low HLA antibody levels seen with the decellularized allografts in this study.^{3,10,11,25,26} Third, histologic confirmation of tissue ingrowth and the long-term biomechanical properties beyond animal studies are not known.⁴ The decellularized allograft may possess unique biomechanical properties that result in unknown extra risk of complications, such as aneurysm or pseudoaneurysm formation, cusp dehiscence, and possible other long-term effects of any differences in compliance. Only a prospective, randomized trial with longer follow-up will most accurately answer these questions. It may be even more difficult to establish superiority or inferiority of nonvalved allograft patches, because there is a low incidence of stenosis with standard nonvalved allograft material. At present, benefits of decellularized nonvalved allograft patches can only been measured clinically by the development of HLA antibodies and the possible detrimental effect that this may have on a patient with regard to allograft function and possible future transplantation. Longer-term experience with these decellularized valves is necessary to balance the cost-benefit relative to standard cryopreserved allografts and determine whether the additional cost and potentially unknown long-term complications are outweighed by the advantages of low immunogenicity and possible improvements in durability.

	References

Top Abstract Patients and methods Results Discussion References

 

1. Cochran RP, Kunzelman KS. Cryopreservation does not alter antigenic expression of aortic allografts. J Surg Res. 1989;46:597–599[Medline]
   
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3. Shaddy RE, Hunter DD, Osborne KA, Lambert LM, Minich LL, Hawkins JA, et al. Prospective analysis of HLA immunogenicity of cryopreserved valved allografts used in pediatric heart surgery. Circulation. 1996;94:1063–1067[Abstract/Free Full Text]
   
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12. McNally RT, Heacox AE, Brockbank KG. Short-term follow-up of cryopreserved allograft valves and valved conduits from the CryoLife clinical registry. Yankah AC, Hetzer R, Miller DC, et al. Cardiac valve allografts 1962-1987. Darmstadt, Germany: Steinkopff Verlag; 1988. p. 323–332
    
13. Heacox AE, McNally RT, Brockbank KG. Factors affecting the viability of cryopreserved allograft heart valves. Yankah AC, Hetzer R, Miller DC, et al. Cardiac valve allografts 1962-1987. Darmstadt, Germany: Steinkopff Verlag; 1988. p. 37–42
    
14. McNally RT, Heacox A, Brockbank KG, Bank HL, inventors. Method for Cryopreserving Heart Valves. Cryolife, Inc., Assignee. Jan 2, 1987, US patent 4,890,457
    
15. The Trial to Reduce Alloimmunization to Platelets Study Group. Leukocyte reduction and ultraviolet B irradiation of platelets to prevent alloimmunization and refractoriness to platelet transfusions. N Engl J Med. 1997;337:1861–1869[Abstract/Free Full Text]
    
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18. O’Brien M, Stafford E, Gardner M, Pohlner P, McGiffin D. A comparison of aortic valve replacement with viable cryopreserved and fresh allograft valves with a note on chromosomal studies. J Thorac Cardiovasc Surg. 1987;94:812–823[Abstract]
    
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21. Hoekstra F, Witvliet M, Knoop C, Akkersdijk G, Jutte N, Bogers A, et al. Donor-specific anti-human leukocyte antigen class I antibodies after implantation of cardiac valve allografts. J Heart Lung Transplant. 1997;16:570–572[Medline]
    
22. Hoekstra FM, Witvliet M, Knoop CY, Wassenaar C, Bogers AJ, Weimar W, et al. Immunogenic human leukocyte antigen class II antigens on human cardiac valves induce specific alloantibodies. Ann Thorac Surg. 1998;66:2022–2026[Abstract/Free Full Text]
    
23. Smith JD, Danskine AJ, Rose ML, Yacoub MH. Specificity of lymphocytotoxic antibodies formed after cardiac transplantation and correlation with rejection episodes. Transplantation. 1992;53:1358–1362[Medline]
    
24. Suciu-Foca N, Reed E, Marboe C, Harris P, Yu PX, Sun YK, et al. The role of anti-HLA antibodies after heart transplantation. Transplantation. 1991;51:716–724[Medline]
    
25. Shaddy RE, Hunter DD, Osborn KA, Hawkins JA, Fuller TC. Persistence of anti-HLA antibodies beyond one year in children receiving cryopreserved valved allografts at surgery. Am J Cardiol. 1997;80:358–359[Medline]
    
26. Shaddy RE, Lambert LM, Fuller TC, Profaizer T, Thompson DD, Baker SI, et al. A prospective randomized trial of azathioprine in children receiving cryopreserved valved allografts for repair of congenital heart defects. Ann Thorac Surg. 2001;71:43–47[Abstract/Free Full Text]
    

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): John A. Hawkins Neal D. Hillman Gregory B. Di Russo Richard V. Williams Robert E. Shaddy Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hawkins, J. A. Articles by Shaddy, R. E. Search for Related Content PubMed PubMed Citation Articles by Hawkins, J. A. Articles by Shaddy, R. E. Related Collections Congenital - acyanotic Congenital - cyanotic Electrophysiology - arrhythmias Related Article