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Ann Thorac Surg 2004;77:1734-1739
© 2004 The Society of Thoracic Surgeons

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Original article: cardiovascular

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

^a Department of Pediatrics, University of Utah School of Medicine and Primary Children's Medical Center, Salt Lake City, Utah, USA
^b Department of Pathology, University of Utah School of Medicine and Primary Children's Medical Center, Salt Lake City, Utah, USA
^c Department of Surgery, University of Utah School of Medicine and Primary Children's Medical Center, Salt Lake City, Utah, USA

Accepted for publication October 8, 2003.

^* Address reprint requests to Dr Shaddy, Department of Cardiology, Suite 1500, Primary Children's Medical Center, 100 North Medical Dr, Salt Lake City, UT 84113, USA
e-mail: robert.shaddy{at}ihc.com

	Abstract

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 
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/m²/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.

	Introduction

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 
The use of both aortic and pulmonary valved allografts in the surgical treatment of congenital heart disease has gained widespread popularity. Allografts are utilized in a variety of corrective and palliative surgeries for congenital heart disease, including reconstruction of the right and left ventricular outflow tracts and aortic arch. Valved and nonvalved allograft tissue implanted at the time of surgical repair of congenital heart defects induces a strong human leukocyte antigen (HLA) antibody response that broadens in reactivity and persists for at least one year after implantation [1–4]. Although the consequences of this antibody response are not well defined, there is concern that immunologic reaction may damage the allograft tissue and thus shorten the "life" of the allograft. Furthermore, in the small number of children who receive allograft tissue at the time of surgery who go on to require heart transplantation, these circulating HLA antibodies will decrease the donor pool and possibly decrease the overall success of transplantation [5, 6]. Thus, attempts to define the role of the HLA antibody response to allograft tissue and to explore safe methods of reducing this immune response are warranted. In a previous prospective, randomized trial, we have shown that azathioprine does not reduce the HLA antibody response to valved allograft implantation in children [7]. Mycophenolic mofetil (MMF) is an immunosuppressant that inhibits the proliferation of both T cells and B cells by blocking the enzyme inosine monophosphate dehydrogenase. Mycophenolic mofetil has been shown in vitro and in vivo to block lymphocyte response to a number of antigens at concentrations of those antigens that do not affect other immune cell lines [8]. Studies in animals and subsequently humans, including a more recent experience in pediatric solid organ transplantation, have confirmed the relative safety and efficacy of MMF as an immunosuppressant [9–12]. The purpose of this current investigation was to perform a pilot study to determine whether MMF can reduce the HLA alloimmune antibody response to valved allograft implantation in children.

	Patients and methods

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 
The study was approved by the Institutional Review Board at the University of Utah Health Sciences Center. Informed consent was obtained from the parent or guardian of each patient, and informed assent was obtained from children 7 years of age or older. All procedures followed were in accordance with institutional guidelines. All patients who were scheduled for surgical repair of a congenital heart defect with the possibility of receiving a cryopreserved valved allograft, and who had not received any previous allograft material, were approached for enrollment. We approached 28 children for enrollment. Thirteen patients refused enrollment: 6 because of concerns of side effects of MMF (infection and[or] gastrointestinal upset); 3 because they did not want blood drawn; 2 because of a possible mild immunodeficiency discovered after enrollment; and 2 gave no reason. Five patients were enrolled but did not receive a valved allograft at surgery. Thus, 10 patients were enrolled and received a valved allograft at surgery. Surgical procedures included tetralogy of Fallot repair (n = 6), repair of aortic stenosis (n = 3, 2 Ross procedures and 1 aortic valve replacement with a valved allograft), and repair of pulmonary atresia with intact ventricular septum (n = 1). We implanted 9 pulmonary, and 1 aortic, valved allografts.

Mycophenolic mofetil was started within 12 hours after completion of surgery. Initially, the medication was given intravenously and then was given orally when the patient was able to take oral medications. The starting dose of MMF (600 mg/m²/dose) was given twice daily. Dosing was adjusted to maintain a drug level of 2 to 5 mg/mL of mycophenolic acid, a metabolite of MMF. The following blood studies were obtained on all patients preoperatively, then one week after surgery and monthly for 3 months: cell blood count, liver function tests (alanine aminotransferase and aspartate aminotransferase), and panel reactive HLA antibody (PRA). The HLA type of all recipients and 6 allograft donors was obtained at the time of surgery. All patients received irradiated and leukocyte-filtered perioperative blood products to prevent sensitization to allogeneic blood cells. Blood products were filtered with Purecell leukocyte reduction filters (Pall Biomedical Products Co, East Hills, NY) and irradiated with ¹³⁷Cs at 30 Gy. After surgery, patients were followed clinically at the discretion of their cardiologist. At each blood draw visit, the patients were specifically asked about any fevers, infections, gastrointestinal problems, or other possible adverse effects. Two patients withdrew before their one-month blood draw: one because of a sinus infection and one because of persistent gastrointestinal upset.

Immunologic testing
We measured each patient's PRA using a technology (LifeMATCH ID [class I + class II], Orchid Diagnostics, Stamford, CT) that utilizes a microarray of up to 100 different color-coded polystyrene microspheres to which have been coupled purified HLA-A, -B, -C, -DR, and DQ locus alloantigens from platelets or lymphoblastoid cell lines derived from up to 100 HLA-select individuals. Five uL of the HLA-bead pool was incubated with 0.02 mL of undiluted patient serum in one well of a 96 well microtiter U-plate; after washing four times, a phycoerythrin-conjugated goat antihuman-IgG was added. The stained beads were then differentiated by dual fluorescence on Luminex 100 fluoroanalyzer (Austin, TX). The relative fluorescent magnitude of bound IgG on each bead population of the microarray was quantified simultaneously. Antibody specificity was assigned using statistical software developed by Orchid Diagnostics (Stamford, CT). We have found this assay to be extremely sensitive and specific. We performed validation of HLA antibody specificity with a large patient serum panel using antiglobulin-cytotoxicity and also a commercial flow cytometry assay. Panel reactive antibody is expressed as the percentage of lymphocyte panel members against which each patient's serum reacts and therefore reflects the breadth of allosensitization against the potential donor population. We measured HLA class I antibodies at 1 month and 3 months after surgery in all patients who received MMF and all control patients. We measured HLA class II antibodies in all MMF patients at 1 month and 3 months after surgery, and in all control patients at 3 months after surgery. However, we were only able to measure HLA class II antibody PRA in 7 of 16 historical controls at 1 month after surgery.

Human leukocyte antigen typing of the allograft was performed in 6 patients from allograft tissue discarded at the time of surgery. Allograft DNA was extracted from minced allograft tissue using the Qiagen DNA purification kit (Genovision, Westchester, PA). The HLA-ABC molecular typing was performed using HLA sequence-specific primer polymerase chain reaction (PCR) kits, and HLA-DR oligotyping was performed using sequence-specific oligonucleotide probe hybridization-enzyme linked immunosorbent assay (SSOPH-ELISA) procedure after PCR amplification (ELPHA, Biotest Diagnostics, Denville, NJ). ABO blood types of the valved allograft and the recipient were available in 6 patients.

We analyzed HLA specificity of each patient's serum to determine if patient HLA antibody specificities were antigen-specific for the incompatibilities expressed on the donor valved allograft.

Statistical analysis
We divided PRA levels into the following categories: none: 0% to 10%; low: 11% to 50%; high: 51% to 100%. For the purpose of comparison, we used historical controls from two of our previous studies with valved allografts [1, 7]. In these previous studies, we measured HLA class I and class II PRA in 16 patients who received valved allografts at the time of surgery. There were no differences between patients who received MMF in this study and historical controls with regard to age at operation or allograft type. However, allograft diameter was smaller in the historical controls than in the patients who received MMF in this study (p = 0.03) (Table 1). Comparisons of PRA levels between patients in this study and historical controls were made at 1 and 3 months after surgery for HLA class I and HLA class II PRA. Because of the statistical concerns of interpreting ² analyses when there are small numbers, we performed comparisons between groups at 1 and 3 months after surgery using a Fischer's exact test comparing PRA levels less than or equal to 50% (none or low) versus more than 50% (high). A p value less than 0.05 was considered statistically significant.

	Results

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

HLA class I PRA
The HLA class I PRA levels were significantly lower at 1 month and 3 months after surgery in patients who received MMF when compared to historical controls. At 1 month after surgery the HLA class I PRA levels in patients treated with MMF showed 6 of 8 patients (75%) with no elevation in PRA, 2 patients (25%) with a low PRA, and no patient with a high PRA. This was significantly lower than the HLA class I PRA levels obtained 1 month after surgery in our previous studies (controls) where 2 of 16 patients (12.5%) had no elevation in PRA, 2 of 16 patients (12.5%) had a low PRA, and 12 of 16 patients (74%) had a high PRA (p = 0.001, Fig 1A). At 3 months after surgery the HLA class I PRA levels in patients treated with MMF showed 2 of 8 patients with no elevation in PRA, 3 patients with a low PRA, and 3 patients with a high PRA. This also was markedly less than our previous studies in which 16 of 16 patients had high HLA class I PRA levels 3 months after surgery (p = 0.001, Fig 1B).

View larger version (23K): [in this window] [in a new window]   Fig 1. (A) Number of patients with each level of HLA class I PRA (no elevation, low PRA, and high PRA) at 1 month after surgery in patients treated with MMF and historical controls. (B) Number of patients with each level of HLA Class I PRA (no elevation, low PRA, and high PRA) at 3 months after surgery in patients treated with MMF and historical controls. = no PRA; = low PRA; = high PRA. (HLA = human leukocyte antigen; MMF = mycophenolic mofetil; PRA = panel reactive antibody.)

View larger version (20K): [in this window] [in a new window]   Fig 2. Number of patients with each level of HLA class II PRA (no elevation, low PRA, and high PRA) at 3 months after surgery in patients treated with MMF and historical controls. = no PRA; = low PRA; = high PRA. (HLA = human leukocyte antigen; MMF = mycophenolic mofetil; PRA = panel reactive antibody.)

Adverse events
One patient developed maxillary sinusitis that was successfully and uneventfully treated with oral antibiotics 3 weeks after surgery. The MMF was stopped at the time of diagnosis of the sinusitis, and the family requested withdrawal from the study at that time. Nausea and vomiting occurred in 3 patients postoperatively after starting MMF. In 2 patients, this was transient and responded to either addition of gastrointestinal medication (1 patient) or addition of gastrointestinal medication and dosage reduction (1 patient). The third patient received medication for nausea and vomiting in addition to dosage reduction without improvement. The MMF was then stopped and resumed at lower dosing given 3 times daily. Despite this, the vomiting persisted and the family requested withdrawal of the patient from the study. No patient had clinically significant increase in liver enzymes or decrease in cell blood counts.

Clinical follow-up
Follow-up is available on all patients from 9 to 19 months after valved allograft implantation. Not all patients have had an echocardiogram. However, no patient has either echocardiographic or clinical evidence of more than mild conduit stenosis or insufficiency.

	Comment

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 
In this study, we have shown the ability to pharmacologically blunt the HLA class I antibody response to valved allograft implantation in children receiving a valved allograft at the time of surgery. We have also shown that this recipient HLA antibody response is directed against HLA antigens on the valved allograft. We and others [1, 4, 13, 14] have previously shown that children demonstrate a vigorous HLA antibody response to a large number of foreign stimuli, including blood products, nonvalved allograft tissue, valved allograft tissue, and cryopreserved venous and arterial hemodialysis grafts. Although the consequences of this donor-specific alloimmune response are still unknown, we believe that the HLA antibody response seen after valved allograft implantation has the potential for a deleterious effect on valved allograft function in a large number of children. Furthermore, although all of the ABO matches between allograft and recipient in this study were fortuitously identical or compatible, this will not occur routinely. However, it has been suggested that ABO incompatibility may not be an important factor with cryopreserved allograft tissue because of the lack of expression of carbohydrate antigens such as blood type on these grafts [15]. Additional nonimmunologic factors, such as sternal compression, younger recipient age, oversizing or undersizing of conduits with anatomic distortion, in addition to ischemic injury may play a crucial role in valved allograft longevity as well [16, 17].

The reduction in HLA antibody response to valved allograft implantation in the current study was achieved with monotherapy using MMF, and the number and severity of adverse effects do not seem excessive. Although the degree of reduction of the HLA antibody response to valved allograft implantation was significant, the majority of patients in this study still had detectable antibody. Thus, it is unknown if the degree of reduction in HLA antibody achieved in this study will have an impact on valved allograft function. It is possible that 3 months of modest immunosuppression with MMF will not be adequate to have a clinical impact on valved allograft function. Further studies will be needed to determine if MMF or other possible immunosuppressants will have any clinical benefit in improving the function of, and prolonging the life of, valved allografts in children.

It is possible that stronger immunosuppression with more agents would reduce the immune response to valved allografts, but the adverse effects of such heavy immunosuppression may be prohibitive. It is likely that the number of adverse effects from immunosuppression would continue to increase significantly with greater immunosuppression. Multiple immunosuppressive medications are used after heart transplantation to block the recipient immune response to the graft. Most institutions utilize a calcineurin inhibitor (tacrolimus or cyclosporine) in addition to either azathioprine or MMF, and in many institutions, corticosteroids. Cyclosporine has been used experimentally in animals and anecdotally in children to block the alloimmune response to allograft tissue [18–20]. However, long-term cyclosporine treatment has significant and unavoidable side effects that are well documented in the transplant literature, including hypertension, renal dysfunction, hirsuitism, gingival hyperplasia, in addition to the ubiquitous concerns of all immunosuppressants such as infection and malignancy. Steroids are not adequate monotherapy for blocking the alloimmune response and also have multiple unavoidable side effects that preclude their use in this setting. Thus, it is encouraging that MMF appears to be at least partially effective with a potentially acceptable adverse effect profile over a 3 month period. The fact that MMF was successful in blunting the HLA alloimmune response to valved allograft implantation, whereas azathioprine was not in our previous study, probably reflects the increased B cell inhibitory effects of MMF compared to azathioprine [7, 8, 21]. MMF has previously been shown to be able to decrease preexisting panel reactive antibodies [22]. It is still unknown whether this brief period of immunosuppression will have any impact on valved allograft function or the ultimate alloimmune response to the graft.

Although experience with MMF as sole immunosuppressive therapy in children is limited, adverse effects seen in adults receiving MMF as sole immunosuppression appear to be uncommon and, in general, self-limiting and responsive to dose adjustments. The most frequent adverse effects of MMF are gastrointestinal and include gastritis, esophagitis, diarrhea, nausea, and vomiting [8, 23, 24]. Following gastrointestinal side effects in frequency are hematologic side effects including leukopenia, thrombocytopenia, neutropenia [25], and anemia [24, 26]. Transient elevation in liver enzymes and cholestasis have been reported with MMF therapy and are generally either self-limiting or responsive to reduction or cessation of the medication [23]. Although an increased risk of infection is always a concern with any immunosuppressive medication, the risk of increased infection with MMF in adults appears to be modest and similar in frequency to other immunosuppressive agents [23].

On the basis of this pilot study in this small number of children, it is not possible to recommend routine use of MMF in children receiving valved allografts at surgery. Many more questions with regard to safety and efficacy need to be answered. For instance, does this short period of immunosuppression translate into improved long-term valved allograft function? Will this short-term reduction of the HLA antibody response persist after discontinuation of MMF? Is a longer course of immunosuppression or a more powerful immunosuppressant regimen necessary or warranted to reduce circulating HLA antibodies and possibly improve valved allograft function? Larger studies with longer follow-up are needed, some of which are underway and(or) planned, before routine use of immunosuppression after valved allograft implantation can be recommended.

	Acknowledgments

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 
This study was an investigator-initiated study by the investigators that was funded in part by Roche Pharmaceuticals. The authors thank Roche Pharmaceuticals for its generous support of this study and the Pediatric Pharmacology Program at the University of Utah for its assistance.

	References

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 

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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): Robert E. Shaddy John A. Hawkins Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Shaddy, R. E. Articles by Hawkins, J. A. Search for Related Content PubMed PubMed Citation Articles by Shaddy, R. E. Articles by Hawkins, J. A. Related Collections Molecular biology