INITIAL AND TRANSIENT C4d-POSITIVE ACUTE HUMORAL REJECTION IN A SENSITIZED CARDIAC GRAFT RECIPIENT MAY TRIGER RECURRENT ACUTE CELLULAR REJECTION

 

J-P. Duong Van Huyen(1), P. Fornes(1), R. Guillemain(2), C. Amrein(2), P. Chevalier(2), C. Latremouille(2), D. Glotz(3), C. Creput(1), D. Nochy(1) and P. Bruneval(1)

Pathology(1), Cardiac Transplantation(2), and Nephrology(3), Hôpital Européen Georges Pompidou, Paris, France

 

Although acute humoral rejection defined by peritubular vascular C4d deposits has been frequently reported in renal transplantation, it seems very rare in heart transplantation. Furthermore, its natural history and consequences remain unclear. We report here such a case.

           

In November 2002, a 37-year-old female patient underwent orthotopic cardiac transplantation for peripartum dilated cardiomyopathy evolving for 18 months. She had 4 children, 2 twins from 2 pregnancies. The cardiomyopathy started in the 9th month of the last pregnancy. Pretransplantation tests showed patient sensitization:  presence of anti-HLA class I and II IgG by ELISA and panel reactive antibodies at 62% by microlymphocytotoxicity. No anti-endothelial or anti-epithelial cell specificities were detected. Intravenous immune globulins (IVIg) (Gammagard, Baxter) regimens did not reverse the sensitization status. The HLA groups were A2, A24; B8, B60; DR7, DR15 for the recipient and A31, 66; B35, 41; DR4, DR7 for the donor. In this sensitized patient, the prospective donor-specific cross-match performed before the transplantation was negative. The recipient had the standard immunosuppression in our institution: induction with Thymoglobulin (Sangstat), together with Mycofenolate Mofetil (3 g/d, through MPA at 3.98 ng/ml), Cyclosporine (200 ng/ml), and prednisone (1 mg/kg/d). The post-transplantation clinical and echocardiographic monitoring remained unremarkable for the 5 months of follow-up. At day 7, the first right ventricle endomyocardial biopsy (EMB) showed an unusual pattern of rejection including dilatation of venules with blood leukocyte accumulation and leukocyte adhesion to the endothelium, rare arteriolitis without fibrin necrosis, and intense C4d deposits in all the interstitial capillaries, a small artery, and the endocardium at immunofluorescence on frozen sections. C3, C1q, and fibrin were positive in some capillaries. IgG was negative. A few arteriolar endothelial cells were activated as shown by strong expression of HLA class II and VCAM-1. Most of the mononuclear cells in venules were CD68-positive macrophages as well as rare interstitial cells, whereas CD3-positive T lymphocytes were absent. Given that pattern of acute humoral vascular rejection, the patient received IV methylprednisone (1 g for 3 d), tacrolimus (targeted to a through level of 15 ng/ml) instead of cyclosporine, and IVIg (80 g for 3 d). Intense C4d capillary deposits persisted up to day 28 (4th EMB) and remained constantly negative thereafter up to 5 months. However, markers of endothelial cell activation (VCAM-1, ELAM-1, and HLA class II expression) increased, from the 2nd EMB, spreading to most of the interstitial capillaries and persisted up to 5 months. At day 10,  ELISA showed the appearance of a donor-specfic antibody (IgG anti-A66). At day 21 (3rd EMB), the 1st cellular acute rejection episode was diagnosed as a grade 3A of ISHLT classification. Its cellular composition was unusual, the CD68-positive macrophages being prominent over the CD3 T lymphocytes. It was successfully treated with Thymoglobulin and IV methylprednisone (1 g for 3 d). At day 75 (7th EMB), a 1B-grade acute rejection episode was detected (the CD68-positive macrophages were still prominent over the CD3 T lymphocytes) and treated with OKT3 (Cilag) and IV methylprednisone (1 g for 3 d). At day 120 (9th EMB), a 3A-grade acute rejection episode was diagnosed showing a classical pattern of prominent CD3-positive T lymphocytes over rare CD68-positive macrophages. An IV methylprednisone (1 g for 3 d) pulse was given and Sirolimus (targeted to a through level of 12 ng/ml) was added to the treatment.

           

This is a case of acute humoral vascular rejection in a sensitized recipient developing an anti-HLA class I response against the cardiac graft. It was characterized by initial and transient C4d deposits in the graft vasculature and persistent endothelial cell activation (strong expression of ELAM-1, VCAM-1, and HLA class II). The EMB monitoring showed 3 episodes of acute cellular rejection despite major immunosuppression. It can be suggested that the initial humoral rejection triggered persistent endothelial cell activation which may in turn be responsible for macrophage and T lymphocyte recruitment and for recurrent episodes of acute cellular rejection.

 

INITIAL AND TRANSIENT C4d-POSITIVE ACUTE HUMORAL REJECTION IN A SENSITIZED CARDIAC GRAFT RECIPIENT MAY TRIGER RECURRENT ACUTE CELLULAR REJECTION

 

Patrick BRUNEVAL

Pathology department. Hôpital Européen Georges Pompidou.

20 rue Leblanc.

75015-Paris. France.

e-mail: patrick.bruneval@hop.egp.hop.ap-hop-paris.fr

fax: +33 1 56 09 38 89

phone: +33 1 56 09 38 60