title: Haptoglobin enhances cardiac transplant rejection.
abstract: BACKGROUND
  Early graft inflammation enhances both acute and chronic rejection of heart transplants, but it is unclear how this inflammation is initiated.
  
  
  OBJECTIVE
  To identify specific inflammatory modulators and determine their underlying molecular mechanisms after cardiac transplantation.
  
  
  RESULTS
  We used a murine heterotopic cardiac transplant model to identify inflammatory modulators of early graft inflammation. Unbiased mass spectrometric analysis of cardiac tissue before and ≤72 hours after transplantation revealed that 22 proteins including haptoglobin, a known antioxidant, are significantly upregulated in our grafts. Through the use of haptoglobin-deficient mice, we show that 80% of haptoglobin-deficient recipients treated with perioperative administration of the costimulatory blocking agent CTLA4 immunoglobulin exhibited >100-day survival of full major histocompatibility complex mismatched allografts, whereas all similarly treated wild-type recipients rejected their transplants by 21 days after transplantation. We found that haptoglobin modifies the intra-allograft inflammatory milieu by enhancing levels of the inflammatory cytokine interleukin-6 and the chemokine MIP-2 (macrophage inflammatory protein 2) but impair levels of the immunosuppressive cytokine interleukin-10. Haptoglobin also enhances dendritic cell graft recruitment and augments antidonor T-cell responses. Moreover, we confirmed that the protein is present in human cardiac allograft specimens undergoing acute graft rejection.
  
  
  CONCLUSIONS
  Our findings provide new insights into the mechanisms of inflammation after cardiac transplantation and suggest that, in contrast to its prior reported antioxidant function in vascular inflammation, haptoglobin is an enhancer of inflammation after cardiac transplantation. Haptoglobin may also be a key component in other sterile inflammatory conditions.
authors: From the Department of Internal Medicine (H.S., E.H., D.N.M., C.K.W., D.R.G.), Department of Immunobiology (H.S., D.N.M., C.K.W., D.R.G.), W.M. Keck Biotechnology Resource Laboratory (C.M.C., L.M.C.), Center for Medical Informatics (C.B.), and Section of Comparative Medicine (I.B.S., C.J.B.), Yale School of Medicine, New Haven, CT; Sciomix, Woodbridge, CT (C.B.); Department of Surgery (D.K.) and Department of Immunology (D.K.), Washington University School of Medicine, St Louis, MO.
authors: Hua
authors: H
authors: Shen
authors: From the Department of Internal Medicine (H.S., E.H., D.N.M., C.K.W., D.R.G.), Department of Immunobiology (H.S., D.N.M., C.K.W., D.R.G.), W.M. Keck Biotechnology Resource Laboratory (C.M.C., L.M.C.), Center for Medical Informatics (C.B.), and Section of Comparative Medicine (I.B.S., C.J.B.), Yale School of Medicine, New Haven, CT; Sciomix, Woodbridge, CT (C.B.); Department of Surgery (D.K.) and Department of Immunology (D.K.), Washington University School of Medicine, St Louis, MO.
authors: Elizabeth
authors: E
authors: Heuzey
authors: From the Department of Internal Medicine (H.S., E.H., D.N.M., C.K.W., D.R.G.), Department of Immunobiology (H.S., D.N.M., C.K.W., D.R.G.), W.M. Keck Biotechnology Resource Laboratory (C.M.C., L.M.C.), Center for Medical Informatics (C.B.), and Section of Comparative Medicine (I.B.S., C.J.B.), Yale School of Medicine, New Haven, CT; Sciomix, Woodbridge, CT (C.B.); Department of Surgery (D.K.) and Department of Immunology (D.K.), Washington University School of Medicine, St Louis, MO.
authors: Daniel N
authors: DN
authors: Mori
authors: From the Department of Internal Medicine (H.S., E.H., D.N.M., C.K.W., D.R.G.), Department of Immunobiology (H.S., D.N.M., C.K.W., D.R.G.), W.M. Keck Biotechnology Resource Laboratory (C.M.C., L.M.C.), Center for Medical Informatics (C.B.), and Section of Comparative Medicine (I.B.S., C.J.B.), Yale School of Medicine, New Haven, CT; Sciomix, Woodbridge, CT (C.B.); Department of Surgery (D.K.) and Department of Immunology (D.K.), Washington University School of Medicine, St Louis, MO.
authors: Christine K
authors: CK
authors: Wong
authors: From the Department of Internal Medicine (H.S., E.H., D.N.M., C.K.W., D.R.G.), Department of Immunobiology (H.S., D.N.M., C.K.W., D.R.G.), W.M. Keck Biotechnology Resource Laboratory (C.M.C., L.M.C.), Center for Medical Informatics (C.B.), and Section of Comparative Medicine (I.B.S., C.J.B.), Yale School of Medicine, New Haven, CT; Sciomix, Woodbridge, CT (C.B.); Department of Surgery (D.K.) and Department of Immunology (D.K.), Washington University School of Medicine, St Louis, MO.
authors: Christopher M
authors: CM
authors: Colangelo
authors: From the Department of Internal Medicine (H.S., E.H., D.N.M., C.K.W., D.R.G.), Department of Immunobiology (H.S., D.N.M., C.K.W., D.R.G.), W.M. Keck Biotechnology Resource Laboratory (C.M.C., L.M.C.), Center for Medical Informatics (C.B.), and Section of Comparative Medicine (I.B.S., C.J.B.), Yale School of Medicine, New Haven, CT; Sciomix, Woodbridge, CT (C.B.); Department of Surgery (D.K.) and Department of Immunology (D.K.), Washington University School of Medicine, St Louis, MO.
authors: Lisa M
authors: LM
authors: Chung
authors: From the Department of Internal Medicine (H.S., E.H., D.N.M., C.K.W., D.R.G.), Department of Immunobiology (H.S., D.N.M., C.K.W., D.R.G.), W.M. Keck Biotechnology Resource Laboratory (C.M.C., L.M.C.), Center for Medical Informatics (C.B.), and Section of Comparative Medicine (I.B.S., C.J.B.), Yale School of Medicine, New Haven, CT; Sciomix, Woodbridge, CT (C.B.); Department of Surgery (D.K.) and Department of Immunology (D.K.), Washington University School of Medicine, St Louis, MO.
authors: Can
authors: C
authors: Bruce
authors: From the Department of Internal Medicine (H.S., E.H., D.N.M., C.K.W., D.R.G.), Department of Immunobiology (H.S., D.N.M., C.K.W., D.R.G.), W.M. Keck Biotechnology Resource Laboratory (C.M.C., L.M.C.), Center for Medical Informatics (C.B.), and Section of Comparative Medicine (I.B.S., C.J.B.), Yale School of Medicine, New Haven, CT; Sciomix, Woodbridge, CT (C.B.); Department of Surgery (D.K.) and Department of Immunology (D.K.), Washington University School of Medicine, St Louis, MO.
authors: Ilya B
authors: IB
authors: Slizovskiy
authors: From the Department of Internal Medicine (H.S., E.H., D.N.M., C.K.W., D.R.G.), Department of Immunobiology (H.S., D.N.M., C.K.W., D.R.G.), W.M. Keck Biotechnology Resource Laboratory (C.M.C., L.M.C.), Center for Medical Informatics (C.B.), and Section of Comparative Medicine (I.B.S., C.J.B.), Yale School of Medicine, New Haven, CT; Sciomix, Woodbridge, CT (C.B.); Department of Surgery (D.K.) and Department of Immunology (D.K.), Washington University School of Medicine, St Louis, MO.
authors: Carmen J
authors: CJ
authors: Booth
authors: From the Department of Internal Medicine (H.S., E.H., D.N.M., C.K.W., D.R.G.), Department of Immunobiology (H.S., D.N.M., C.K.W., D.R.G.), W.M. Keck Biotechnology Resource Laboratory (C.M.C., L.M.C.), Center for Medical Informatics (C.B.), and Section of Comparative Medicine (I.B.S., C.J.B.), Yale School of Medicine, New Haven, CT; Sciomix, Woodbridge, CT (C.B.); Department of Surgery (D.K.) and Department of Immunology (D.K.), Washington University School of Medicine, St Louis, MO.
authors: Daniel
authors: D
authors: Kreisel
authors: From the Department of Internal Medicine (H.S., E.H., D.N.M., C.K.W., D.R.G.), Department of Immunobiology (H.S., D.N.M., C.K.W., D.R.G.), W.M. Keck Biotechnology Resource Laboratory (C.M.C., L.M.C.), Center for Medical Informatics (C.B.), and Section of Comparative Medicine (I.B.S., C.J.B.), Yale School of Medicine, New Haven, CT; Sciomix, Woodbridge, CT (C.B.); Department of Surgery (D.K.) and Department of Immunology (D.K.), Washington University School of Medicine, St Louis, MO. daniel.goldstein@yale.edu.
authors: Daniel R
authors: DR
authors: Goldstein
mesh_terms: D000069594:Abatacept; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D054426:Chemokine CXCL2 / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006084:Graft Rejection / Q000097:blood / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D006242:Haptoglobins / Q000276:immunology* / Q000378:metabolism; D016027:Heart Transplantation / Q000009:adverse effects*; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007249:Inflammation / Q000097:blood / Q000276:immunology* / Q000473:pathology; D018836:Inflammation Mediators / Q000097:blood / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008213:Lymphocyte Activation; D008297:Male; D013058:Mass Spectrometry; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics; D009206:Myocardium / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D040901:Proteomics / Q000379:methods; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D013997:Time Factors
chemical_list: D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; C485359:HP protein, human; D006242:Haptoglobins; C556062:IL10 protein, mouse; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D018836:Inflammation Mediators; D015850:Interleukin-6; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C577686:interleukin-6, mouse; D016753:Interleukin-10; D000069594:Abatacept; D007371:Interferon-gamma
keywords: immunology; inflammation; rejection; transplantation