Two-year reduction of panel reactive human leukocyte antigen antibodies in children receiving mycophenolate mofetil after valved allograft placement.

Allografts used in the repair of congenital heart defects in children induce a persistent broad HLA antibody response. We have previously shown that a 3-month course of mycophenolic mofetil (MMF) significantly reduces the HLA class I antibody response to valved allograft implantation in children. The purpose of this study was to determine if this reduction in HLA antibody persists after discontinuation of MMF. We conducted follow-up (mean 2 +/- 0.5 years) of seven patients who had received allograft placement for repair of congenital heart defects. These patients received 3 months of immunosuppression with MMF following allograft implantation. When compared to historical controls, patients who received MMF following surgery showed a significantly decreased HLA class I antibody response at 2 years postimplantation. This study demonstrates the ability to persistently alter the HLA class I antibody response using 3 months of MMF following allograft implantation in children.

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

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.

Early failure of a tricuspid valve replacement with a mitral valve homograft in a heart transplant recipient.

A 24-year-old woman experienced severe tricuspid valve regurgitation 6 years after heart transplantation. Tricuspid valve replacement was performed using a cryopreserved mitral valve homograft. Severe tricuspid valve regurgitation recurred within 4 months, associated with an increase in the panel reactive antibody titers from zero to 72%. Tricuspid valve replacement was repeated with a porcine bioprosthesis with excellent recovery and function for >2 years. The mitral valve homograft displayed inflammatory features consistent with humoral immune-mediated destruction.

Mycophenolic mofetil reduces the HLA antibody response of children to valved allograft implantation.

BACKGROUND: Valved allografts induce a brisk, broadly reactive human leukocyte antigen (HLA) antibody response in children after implantation. Mycophenolic mofetil (MMF) is a powerful immunosuppressant that inhibits the proliferation of both T cells and B cells and has been reported to possibly reduce HLA panel reactive antibody (PRA) in sensitized transplant recipients. METHODS: The purpose of this study was to determine whether MMF can blunt the HLA antibody response to valved allografts in children. Eight patients completed (of 28 approached) a pilot study to determine the effects of 3 months of twice daily MMF (600 mg/m(2)/dose) on the HLA antibody response measured before surgery, at 1 month, and at 3 months after implantation. Patients were 7.5 +/- 4 yrs old (mean +/- standard deviation [SD]), with 5 patients undergoing repair of tetralogy of Fallot, 2 Ross procedures, and 1 aortic valve replacement. RESULTS: In contrast to historical controls with a virtual 100% HLA class I PRA response to valved allograft implantation, MMF markedly decreased the HLA class I antibody response at 1 and 3 months postimplantation. In 6 cases where the HLA type of the donor was defined, PRA specificity correlated with incompatible antigens on the allograft. One patient withdrew after 2 weeks due to a sinus infection that was successfully treated with oral antibiotics, and 3 patients had a transient adverse effect of postoperative vomiting. CONCLUSIONS: This study demonstrates the ability to pharmacologically abrogate the HLA class I antibody response to valved allograft implantation in children using MMF.

HLA mismatching within or outside of cross-reactive groups (CREGs) is associated with similar outcomes after unrelated hematopoietic stem cell transplantation.

The National Marrow Donor Program maintains a registry of volunteer donors for patients in need of a hematopoietic stem cell transplantation. Strategies for selecting a partially HLA-mismatched donor vary when a full match cannot be identified. Some transplantation centers limit the selection of mismatched donors to those sharing mismatched antigens within HLA-A and HLA-B cross-reactive groups (CREGs). To assess whether an HLA mismatch within a CREG group ("minor") may result in better outcome than a mismatch outside CREG groups ("major"), we analyzed validated outcomes data from 2709 bone marrow and peripheral blood stem cell transplantations. Three-hundred and ninety-six pairs (15%) were HLA-DRB1 allele matched but had an antigen-level mismatch at HLA-A or HLA-B. Univariate and multivariate analyses of engraftment, graft-versus-host disease, and survival showed that outcome is not significantly different between minor and major mismatches (P = .47, from the log-rank test for Kaplan-Meier survival). However, HLA-A, HLA-B, and HLA-DRB1 allele-matched cases had significantly better outcome than mismatched cases (P < .001). For patients without an HLA match, the selection of a CREG-compatible donor as tested does not improve outcome.

Prevalence and risks of allosensitization in HeartMate left ventricular assist device recipients: the impact of leukofiltered cellular blood product transfusions.

OBJECTIVE: Allosensitization of left ventricular assist device recipients has been associated with perioperative transfusion of cellular blood products. The relative sensitizing contribution of leukofiltered cellular blood products, however, remains unclear. We investigated the pattern of sensitization in left ventricular assist device recipients in relation to cellular blood product transfusions received. METHODS: Seventy-one consecutive nonsensitized recipients of the HeartMate left ventricular assist device (Thoratec Corporation, Pleasanton, Calif) as a bridge to transplantation were reviewed. Panel-reactive HLA antibody levels at consecutive times after device implantation were correlated with perioperative cellular blood product transfusions. RESULTS: Fifty-four patients received leukofiltered cellular blood products (transfused), whereas 17 patients received only fresh-frozen plasma (nontransfused). Among nontransfused patients, 58.8% (10/17) became sensitized during mechanical support, versus 35.2% of transfused patients (19/54, P = .15). There was a trend toward more sensitization during the 12 weeks after device placement in nontransfused patients. Kaplan-Meier analysis revealed significantly more sensitization in nontransfused patients than in transfused patients, despite equal rates of transplantation (P = .05). A dose-response analysis revealed significant trends toward less sensitization and lower peak panel-reactive antibody level with more cellular blood product transfusions (P = .04). Multivariate Cox regression revealed only increasing transfusions to be associated with a reduced risk of sensitization (hazard ratio 0.18, P = .01). CONCLUSIONS: Sensitization becomes more prevalent with increasing length of support. Avoidance of perioperative leukocyte-filtered cellular blood product transfusions does not decrease the incidence or degree of HLA sensitization. Conversely, cellular blood product transfusions may be associated with lessened alloimmunization and may mitigate the sensitization seen in recipients of the HeartMate left ventricular assist device as a bridge to transplantation.

Low-dose prophylactic intravenous immunoglobulin does not prevent HLA sensitization in left ventricular assist device recipients.

BACKGROUND: The use of left ventricular assist devices is associated with human leukocyte antigen (HLA) allosensitization. We investigated whether prophylactic treatment with low-dose intravenous immunoglobulin (IVIG), analogous to the use of IgG anti-D (anti-Rh) in preventing Rh immunization, can abrogate HLA allosensitization after left ventricular assist device implantation. METHODS: We retrospectively reviewed the data from 84 consecutive heart failure patients who underwent implantation of a left ventricular assist device as a bridge to transplantation. After implantation, panel reactive antibody (PRA) was measured biweekly to assess sensitization (defined by PRA > 10%). Patients who were sensitized before left ventricular assist device implantation were excluded from further analysis (n = 12). Patients who either did not require perioperatively transfusions of cellular blood products or received other immunomodifying regimens were also excluded from further analysis (n = 21). The rest of the patients were divided into two groups based on whether they received IVIG, 10 g daily for 3 days (IVIG group, n = 26; non-IVIG group, n = 25). The decision as to whether patients received IVIG was not randomized but was based on surgeon preference. RESULTS: The sensitization rates (expressed as ratio of sensitized patients to total patients at risk) in the two groups were similar at consecutive time points (2, 4, 6, 8, 12, 20 weeks) after left ventricular assist device implantation. Also, mean PRA at the same time points did not differ between the two groups. Overall, 34.6% (9 of 26) of the IVIG group became sensitized during mechanical support, compared with 32% (8 of 25) of the non-IVIG group (p = 1.0). A PRA of 90% or greater (high-degree sensitization) occurred in 15.3% (4 of 26) of the IVIG group and 12.0% (3 of 25) of the non-IVIG group (p = 0.5). CONCLUSIONS: The use of low-dose prophylactic IVIG after left ventricular assist device implantation affects neither the incidence nor the severity of HLA allosensitization.

The sensitized pediatric heart transplant candidate: causes, consequences, and treatment options.

Sensitization to HLA antigens and the subsequent development of HLA antibodies in children under consideration for heart transplantation is a significant impediment to survival after listing. This is related both to the frequent need for prospective donor-specific crossmatching (thus limiting donor availability and increasing pretransplant morbidity and mortality), and to the increased risk of adverse outcomes after transplantation. This article will review the scope of this problem in children under consideration for heart transplantation, the different methods available for diagnosing HLA sensitization, the known causes of HLA sensitization, the consequences of these preformed antibodies on outcomes before and after heart transplantation, and the different methods of preventing and treating this sensitization that are currently available. Improved methods of diagnosing, preventing, and treating this problem can only lead to better outcomes for children who require heart transplantation.

Panel-reactive antibodies late after allograft implantation in children.

BACKGROUND: Circulating human leukocyte antigen (HLA) panel-reactive antibodies (PRA > 10%) have been independently associated with increased risk of rejection and mortality in patients who undergo cardiac transplantation. Cryopreserved allografts used to repair heart defects induce broadly reactive HLA antibodies in children that persist for an undetermined duration of time. The purpose of this study was to prospectively determine the level of HLA sensitization several years after implantation of cryopreserved allografts in children. METHODS: We conducted late follow-up of 13 children previously screened for PRA before and after implantation of valved and nonvalved allografts who are alive and free from allograft replacement. Panel-reactive antibodies against HLA class I and II antigens were determined using flow cytometry and classified as high reactive (>50% PRA), low reactive (11% to 50%), or absent (0% to 10%). Follow-up PRA was compared with PRA obtained 3 months after initial allograft implantation. RESULTS: Elevated HLA class I PRA persisted at late follow-up in 12 of 13 children, although it decreased significantly from high to low or from low to absent in 12 of 13 patients (p < 0.001). Elevated HLA class II PRA persisted at late follow-up in 6 of 13 children (46%) and had decreased significantly from prior levels (p = 0.011). CONCLUSIONS: Circulating HLA antibodies induced by cryopreserved allograft tissue persist up to 8 years after implantation although they decrease with time. Therefore, children who have received cryopreserved allografts before cardiac transplantation may be at greater risk for transplant rejection.