Preformed IgG Antibodies Against Major Histocompatibility Complex Class II Antigens Are Major Risk Factors for High-grade Cellular Rejection in Recipients of Heart Transplantation

Itescu, Silviu; Tung, Thomas; Burke, Elizabeth; Weinberg, Alan; Moazami, Nader; Artrip, John H.; Suciu‐Foca, Nicole; Rose, Eric A.; Öz, Mehmet C.; Michler, Robert E.

doi:10.1161/01.cir.98.8.786

Cited by 143 publications

(95 citation statements)

References 13 publications

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“…Among the adverse post transplant events are acute cellular rejection, decreased longterm graft survival, increased mortality and accelerated coronary heart disease (17)(18)(19). One study found that preformed anti IgG antibodies directed against MHC Class II antigens were a major risk factor for early and more frequent cellular rejection episodes (20).…”

Section: Discussionmentioning

confidence: 99%

Evidence That Humoral Allograft Rejection in Lung Transplant Patients Is Not Histocompatibility Antigen-Related

Magro¹,

Klinger²,

Adams³

et al. 2003

American Journal of Transplantation

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We have recently recognized humoral rejection (HR) in lung allograft recipients and its association with acute and chronic graft dysfunction. We have shown that C4d, a stable marker of classic complement activation, is deposited in lung allografts, correlating with clinical rejection and parenchymal injury. The antigenic target may be endothelium in the setting of recurrent acute rejection while varying components of the bronchial wall may be important in chronic graft dysfunction. We sought to establish whether there is a role for antibodies with histocompatibility antigen specificity in the lung humoral allograft phenomenon. Flow cytometric and ELISA assays to assess donor-specific antigens were conducted on sera from 25 lung transplant recipients who had experienced one or more episodes of clinical rejection; in addition, the serum samples were tested for evidence of antiendothelial cell antibody activity. Morphologically, each case had biopsies showing septal capillary injury with significant deposits of immunoreactants with microvascular localization and positive indirect immunofluorescent antiendothelial cell antibody assay. Panel-reactive antibody testing showed absence of MHC Class I/II alloantibodies; ELISA based crossmatch detecting donor-specific MHC Class I/II specific antibodies was negative. HR can occur in the absence of antibodies with HLA specificity; antigenic targets may be of endothelial cell origin.

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Section: Discussionmentioning

confidence: 99%

Evidence That Humoral Allograft Rejection in Lung Transplant Patients Is Not Histocompatibility Antigen-Related

Magro¹,

Klinger²,

Adams³

et al. 2003

American Journal of Transplantation

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“…Preformed anti-donor class II antibodies increase the risk of transplant failure [1][2][3][4][5][6][7][8][9] and the post-transplant development of anti-class II antibodies is associated with a higher incidence of acute and chronic rejection [10][11][12][13][14][15][16][17][18][19] Current class II matching strategies for kidney transplantation consider only the HLA-DR antigens controlled by the DRB1 locus but mismatching for HLA-DQ and HLA-DP may also lead to lower graft survival rates [20][21][22][23][24][25]. Newer serum screening methods such as ELISA, Flow Cytometry and Luminex have greatly enhanced the detection of anti-HLA-DQ and HLA-DP antibodies and their association with transplant rejection [2,7,[26][27][28][29].…”

Section: Introductionmentioning

confidence: 99%

Retransplant candidates have donor-specific antibodies that react with structurally defined HLA-DR,DQ,DP epitopes

Duquesnoy

Awadalla

Lomago

et al. 2008

Transplant Immunology

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This report describes a detailed analysis how donor-specific HLA class II epitope mismatching affects antibody reactivity patterns in 75 solid organ transplant recipients with an in situ allograft and who were considered for retransplantation. Sera were tested for antibodies in a sensitive antigenbinding assay (Luminex) with single class II alleles. Their reactivity was analyzed with HLAMatchmaker, a structural matching algorithm that considers so-called eplets to define epitopes recognized by antibodies. Only 24% of the patients showed donor-specific anti-DRB1 antibodies and there was a significant correlation with a low number of mismatched DRB1 eplets. This low detection rate of anti-DRB1 antibodies may also be due to allograft absorption. In contrast, antibodies to DRB3/4/5 mismatches were more common. Especially, 83% of the DRB4 (DR53) mismatches resulted in detectable antibodies against an eplet uniquely found on DR53 antigens. Donor-specific DQB mismatches led to detectable anti-DQB antibodies with a frequency of 87%. Their specificity correlated with eplets uniquely found on DQ1-4. The incidence of antibodies induced by 2-digit DQA mismatches was 64% and several eplets appeared to play a dominant role. These findings suggest that both α and β chains of HLA-DQ heterodimers have immunogenic epitopes that can elicit specific antibodies. About one-third of the sera had anti-DP antibodies; they reacted primarily with two DPB eplets and an allelic pair of DPA eplets.These data demonstrate that HLA class II reactive sera display distinct specificity patterns associated with structurally defined epitopes on different HLA-D alleles.

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“…5,21,22 In addition to histologic examination, one biopsy fragment was placed in medium supplemented with recombinant IL-2, and lymphocyte growth assay was performed as previously described. 5,21 Detection of Anti-HLA Antibodies After transplantation, sera were obtained from all patients at risk for sensitization on the day of initial listing as UNOS status I for transplantation and then every 2 weeks until transplantation. After transplantation, sera were obtained from all patients with each biopsy.…”

Section: Endomyocardial Biopsies and Lymphocyte Growth Assaymentioning

confidence: 99%

“…Sera were screened for the presence of lymphocytotoxic antibodies against a panel of HLA class I and II antigens, as previously described. 5,21 …”

Section: Endomyocardial Biopsies and Lymphocyte Growth Assaymentioning

confidence: 99%

“…In addition, the presence of preformed anti-HLA antibodies predicts poorer long-term outcome, including increased cellular rejections, earlier onset of transplant coronary artery disease (TCAD), and decreased long-term graft survival compared with nonsensitized patients treated with standard triple immunosuppressive regimens. 3,4 These complications seem to be related primarily to the presence of preformed antibodies against allogeneic HLA class II molecules 5 and may reflect an underlying state of CD4 T-cell allosensitization to class II antigens.…”

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confidence: 99%

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Intravenous Pulse Administration of Cyclophosphamide Is an Effective and Safe Treatment for Sensitized Cardiac Allograft Recipients

et al. 2002

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Background-The proportion of cardiac transplant recipients with preexisting sensitization to HLA alloantigens has been increasing. Sensitization prolongs duration to obtaining a donor and predicts poorer long-term allograft survival because of increased risk of cellular rejections. We investigated the effect of cyclophosphamide pulse therapy in sensitized cardiac allograft recipients. Methods and Results-Pretransplant and posttransplant outcomes were compared between 88 cardiac allograft recipients at risk for sensitization and 26 sensitized recipients treated with intravenous cyclophosphamide pulse therapy together with intravenous immune globulin before transplant and as part of a cyclosporine-based triple immunosuppressive regimen after transplant. Preformed IgG anti-HLA antibodies predicted longer duration to transplantation, earlier cellular rejection, and 2.7-fold higher cumulative rejection frequency (Pϭ0.002). Before transplant, cyclophosphamide reduced waiting time and mortality to levels in nonsensitized patients. After transplant, cyclophosphamide prevented induction of IgG anti-HLA class II antibodies and interleukin-2 receptor-positive T-cell outgrowth from biopsy sites (both PϽ0.01), prolonged the rejection-free interval (Pϭ0.009), and reduced cumulative rejections to levels in nonsensitized patients (Pϭ0.003). By multivariable analysis, the risk of rejection was 3.7-fold higher in patients treated with mycophenolate mofetil than patients treated with cyclophosphamide (Pϭ0.019). There were no differences in infectious or other significant complications. Conclusions-Immunosuppression incorporating intravenous cyclophosphamide before and after transplantation is safe and highly effective in sensitized cardiac transplant recipients. When used after transplantation as part of triple immunosuppression, cyclophosphamide is superior to mycophenolate mofetil in reducing rejection. The mechanism may involve prevention of diversification of the recipient immune response to donor HLA class II molecules.

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Preformed IgG Antibodies Against Major Histocompatibility Complex Class II Antigens Are Major Risk Factors for High-grade Cellular Rejection in Recipients of Heart Transplantation

Cited by 143 publications

References 13 publications

Evidence That Humoral Allograft Rejection in Lung Transplant Patients Is Not Histocompatibility Antigen-Related

Evidence That Humoral Allograft Rejection in Lung Transplant Patients Is Not Histocompatibility Antigen-Related

Retransplant candidates have donor-specific antibodies that react with structurally defined HLA-DR,DQ,DP epitopes

Intravenous Pulse Administration of Cyclophosphamide Is an Effective and Safe Treatment for Sensitized Cardiac Allograft Recipients

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