Abstract
To determine the pattern of cellular expression of donor MHC class I and class II antigens during the course of rat cardiac allograft rejection, ACI cardiac allografts transplanted to BN recipients were examined from day 2 to day 6 using immunohistologic and immunoelectron microscopic methods. We used both monomorphic and donor-specific mouse anti-rat MHC class I and class II mAbs in this study. In normal ACI hearts, MHC class I reactivity was confined to the vascular endothelium and to interstitial cells. Ongoing rejection was characterized by an increased donor MHC class I staining intensity of microvascular endothelium and induction of donor class I surface reactivity on cardiac myofibers. Donor MHC class II reactivity was exclusively confined to interstitial dendritic cells (IDC) in both normal ACI hearts and in rejecting allografts, although rejection was associated with marked fluctuations in class II IDC frequency. An early numerical depression in class II IDC present in both allografts and syngeneic heart grafts was attributed to a direct effect of the transplantation procedure. By days 3-4, allografts showed an absolute overall increase in donor class II IDC frequency, which was associated with the presence of multiple localized high-density IDC-lymphocyte aggregates. The lymphocytes present in the focal areas were predominantly of the class II-reactive Th cell subpopulation. These aggregates may thus represent the in vivo homologue of dendritic cell-lymphocyte clustering, which has been shown to be required for primary class II allosensitization in the rat and mouse in vitro. During the late phase of rejection, there was a marked numerical fall in donor class II IDC, which correlated with extensive overall graft destruction. This study has shown that acute rat cardiac allograft rejection can occur in the absence of donor MHC class II expression by allograft vascular endothelium and cardiac myofibers. The IDC, which are believed to represent the principal class II alloantigen presenting cells in the rat heart, remain the sole class II-expressing cellular constituents of the graft throughout the course of rejection.
Full Text
The Full Text of this article is available as a PDF (1.5 MB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Appleyard S. T., Dunn M. J., Dubowitz V., Rose M. L. Increased expression of HLA ABC class I antigens by muscle fibres in Duchenne muscular dystrophy, inflammatory myopathy, and other neuromuscular disorders. Lancet. 1985 Feb 16;1(8425):361–363. doi: 10.1016/s0140-6736(85)91384-4. [DOI] [PubMed] [Google Scholar]
- Austyn J. M., Steinman R. M., Weinstein D. E., Granelli-Piperno A., Palladino M. A. Dendritic cells initiate a two-stage mechanism for T lymphocyte proliferation. J Exp Med. 1983 Apr 1;157(4):1101–1115. doi: 10.1084/jem.157.4.1101. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Benson E. M., Colvin R. B., Russell P. S. Induction of IA antigens in murine renal transplants. J Immunol. 1985 Jan;134(1):7–9. [PubMed] [Google Scholar]
- Cerf-Bensussan N., Schneeberger E. E., Bhan A. K. Immunohistologic and immunoelectron microscopic characterization of the mucosal lymphocytes of human small intestine by the use of monoclonal antibodies. J Immunol. 1983 Jun;130(6):2615–2622. [PubMed] [Google Scholar]
- Czitrom A. A., Sunshine G. H., Reme T., Ceredig R., Glasebrook A. L., Kelso A., MacDonald H. R. Stimulator cell requirements for allospecific T cell subsets: specialized accessory cells are required to activate helper but not cytolytic T lymphocyte precursors. J Immunol. 1983 Feb;130(2):546–550. [PubMed] [Google Scholar]
- Daar A. S., Fuggle S. V., Fabre J. W., Ting A., Morris P. J. The detailed distribution of HLA-A, B, C antigens in normal human organs. Transplantation. 1984 Sep;38(3):287–292. doi: 10.1097/00007890-198409000-00018. [DOI] [PubMed] [Google Scholar]
- Farr A. G., Nakane P. K. Cells bearing Ia antigens in the murine thymus. An ultrastructural study. Am J Pathol. 1983 Apr;111(1):88–97. [PMC free article] [PubMed] [Google Scholar]
- Flores R. V., Gilmer P. J. Differential recognition and lysis of EL4 target cells by cytotoxic T cells: differences in H-2Kb antigenic density and cytoskeletal proteins. J Immunol. 1984 Jun;132(6):2767–2774. [PubMed] [Google Scholar]
- Forbes R. D., Guttmann R. D., Gomersall M., Hibberd J. Leukocyte subsets in first-set rat cardiac allograft rejection. A serial immunohistologic study using monoclonal antibodies. Transplantation. 1983 Dec;36(6):681–686. doi: 10.1097/00007890-198336060-00019. [DOI] [PubMed] [Google Scholar]
- Fukumoto T., McMaster W. R., Williams A. F. Mouse monoclonal antibodies against rat major histocompatibility antigens. Two Ia antigens and expression of Ia and class I antigens in rat thymus. Eur J Immunol. 1982 Mar;12(3):237–243. doi: 10.1002/eji.1830120313. [DOI] [PubMed] [Google Scholar]
- Giacomini P., Aguzzi A., Pestka S., Fisher P. B., Ferrone S. Modulation by recombinant DNA leukocyte (alpha) and fibroblast (beta) interferons of the expression and shedding of HLA- and tumor-associated antigens by human melanoma cells. J Immunol. 1984 Sep;133(3):1649–1655. [PubMed] [Google Scholar]
- Green J., Jotte R. Interactions between T helper cells and dendritic cells during the rat mixed lymphocyte reaction. J Exp Med. 1985 Nov 1;162(5):1546–1560. doi: 10.1084/jem.162.5.1546. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Groenewegen G., Buurman W. A., van der Linden C. J. Lymphokine dependence of in vivo expression of MHC class II antigens by endothelium. Nature. 1985 Jul 25;316(6026):361–363. doi: 10.1038/316361a0. [DOI] [PubMed] [Google Scholar]
- Guttmann R. D. Genetics of acute rejection of rat cardiac allografts and a model of hyperacute rejection. Transplantation. 1974 Apr;17(4):383–386. doi: 10.1097/00007890-197404000-00007. [DOI] [PubMed] [Google Scholar]
- Hall B. M., Bishop G. A., Duggin G. G., Horvath J. S., Philips J., Tiller D. J. Increased expression of HLA-DR antigens on renal tubular cells in renal transplants: relevance to the rejection response. Lancet. 1984 Aug 4;2(8397):247–251. doi: 10.1016/s0140-6736(84)90297-6. [DOI] [PubMed] [Google Scholar]
- Hanafusa T., Pujol-Borrell R., Chiovato L., Russell R. C., Doniach D., Bottazzo G. F. Aberrant expression of HLA-DR antigen on thyrocytes in Graves' disease: relevance for autoimmunity. Lancet. 1983 Nov 12;2(8359):1111–1115. doi: 10.1016/s0140-6736(83)90628-1. [DOI] [PubMed] [Google Scholar]
- Hart D. N., Fabre J. W. Demonstration and characterization of Ia-positive dendritic cells in the interstitial connective tissues of rat heart and other tissues, but not brain. J Exp Med. 1981 Aug 1;154(2):347–361. doi: 10.1084/jem.154.2.347. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jefferies W. A., Green J. R., Williams A. F. Authentic T helper CD4 (W3/25) antigen on rat peritoneal macrophages. J Exp Med. 1985 Jul 1;162(1):117–127. doi: 10.1084/jem.162.1.117. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Klareskog L., Forsum U., Peterson P. A. Hormonal regulation of the expression of Ia antigens on mammary gland epithelium. Eur J Immunol. 1980 Dec;10(12):958–963. doi: 10.1002/eji.1830101212. [DOI] [PubMed] [Google Scholar]
- Lindahl P., Gresser I., Leary P., Tovey M. Interferon treatment of mice: enhanced expression of histocompatibility antigens on lymphoid cells. Proc Natl Acad Sci U S A. 1976 Apr;73(4):1284–1287. doi: 10.1073/pnas.73.4.1284. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mayrhofer G., Schon-Hegrad M. A. Ia antigens in rat kidney, with special reference to their expression in tubular epithelium. J Exp Med. 1983 Jun 1;157(6):2097–2109. doi: 10.1084/jem.157.6.2097. [DOI] [PMC free article] [PubMed] [Google Scholar]
- McKenzie J. L., Beard M. E., Hart D. N. The effect of donor pretreatment on interstitial dendritic cell content and rat cardiac allograft survival. Transplantation. 1984 Oct;38(4):371–376. doi: 10.1097/00007890-198410000-00011. [DOI] [PubMed] [Google Scholar]
- Milton A. D., Fabre J. W. Massive induction of donor-type class I and class II major histocompatibility complex antigens in rejecting cardiac allografts in the rat. J Exp Med. 1985 Jan 1;161(1):98–112. doi: 10.1084/jem.161.1.98. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mukai K., Rosai J., Burgdorf W. H. Localization of factor VIII-related antigen in vascular endothelial cells using an immunoperoxidase method. Am J Surg Pathol. 1980 Jun;4(3):273–276. doi: 10.1097/00000478-198006000-00008. [DOI] [PubMed] [Google Scholar]
- Nakamura M., Manser T., Pearson G. D., Daley M. J., Gefter M. L. Effect of IFN-gamma on the immune response in vivo and on gene expression in vitro. 1984 Jan 26-Feb 1Nature. 307(5949):381–382. doi: 10.1038/307381a0. [DOI] [PubMed] [Google Scholar]
- Ono K., Lindsey E. S. Improved technique of heart transplantation in rats. J Thorac Cardiovasc Surg. 1969 Feb;57(2):225–229. [PubMed] [Google Scholar]
- Ozato K., Mayer N., Sachs D. H. Hybridoma cell lines secreting monoclonal antibodies to mouse H-2 and Ia antigens. J Immunol. 1980 Feb;124(2):533–540. [PubMed] [Google Scholar]
- Parthenais E., Soots A., Nemlander A., von Willebrand E., Häyry P. Immunogenicity of allograft components. II. Relative immunogenicity of rat kidney parenchymal versus "passenger" cells. Cell Immunol. 1981 Jan 1;57(1):92–98. doi: 10.1016/0008-8749(81)90123-4. [DOI] [PubMed] [Google Scholar]
- Pober J. S., Gimbrone M. A., Jr, Cotran R. S., Reiss C. S., Burakoff S. J., Fiers W., Ault K. A. Ia expression by vascular endothelium is inducible by activated T cells and by human gamma interferon. J Exp Med. 1983 Apr 1;157(4):1339–1353. doi: 10.1084/jem.157.4.1339. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rabin B. S., Griffith B. P., Hardesty R. L. Vascular endothelial cell HLA-DR antigen and myocyte necrosis in human allograft rejection. J Heart Transplant. 1985 May;4(3):293–295. [PubMed] [Google Scholar]
- Skoskiewicz M. J., Colvin R. B., Schneeberger E. E., Russell P. S. Widespread and selective induction of major histocompatibility complex-determined antigens in vivo by gamma interferon. J Exp Med. 1985 Nov 1;162(5):1645–1664. doi: 10.1084/jem.162.5.1645. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sobel R. A., Blanchette B. W., Bhan A. K., Colvin R. B. The immunopathology of experimental allergic encephalomyelitis. II. Endothelial cell Ia increases prior to inflammatory cell infiltration. J Immunol. 1984 May;132(5):2402–2407. [PubMed] [Google Scholar]
- Steeg P. S., Moore R. N., Johnson H. M., Oppenheim J. J. Regulation of murine macrophage Ia antigen expression by a lymphokine with immune interferon activity. J Exp Med. 1982 Dec 1;156(6):1780–1793. doi: 10.1084/jem.156.6.1780. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Steiniger B., Klempnauer J., Wonigeit K. Altered distribution of class I and class II MHC antigens during acute pancreas allograft rejection in the rat. Transplantation. 1985 Sep;40(3):234–239. doi: 10.1097/00007890-198509000-00002. [DOI] [PubMed] [Google Scholar]
- Steiniger B., Klempnauer J., Wonigeit K. Phenotype and histological distribution of interstitial dendritic cells in the rat pancreas, liver, heart, and kidney. Transplantation. 1984 Aug;38(2):169–174. doi: 10.1097/00007890-198408000-00016. [DOI] [PubMed] [Google Scholar]
- Steinman R. M., Cohn Z. A. Identification of a novel cell type in peripheral lymphoid organs of mice. I. Morphology, quantitation, tissue distribution. J Exp Med. 1973 May 1;137(5):1142–1162. doi: 10.1084/jem.137.5.1142. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Steinman R. M., Gutchinov B., Witmer M. D., Nussenzweig M. C. Dendritic cells are the principal stimulators of the primary mixed leukocyte reaction in mice. J Exp Med. 1983 Feb 1;157(2):613–627. doi: 10.1084/jem.157.2.613. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wadgymar A., Urmson J., Baumal R., Halloran P. F. Changes in Ia expression in mouse kidney during acute graft-vs-host disease. J Immunol. 1984 Apr;132(4):1826–1832. [PubMed] [Google Scholar]
- de Waal R. M., Bogman M. J., Maass C. N., Cornelissen L. M., Tax W. J., Koene R. A. Variable expression of Ia antigens on the vascular endothelium of mouse skin allografts. Nature. 1983 Jun 2;303(5916):426–429. doi: 10.1038/303426a0. [DOI] [PubMed] [Google Scholar]