Abstract
Aims—To determine which inflammatory and immune pathways are implicated in the development of chronic graft versus host disease (GvHD) and whether differences between these pathways are responsible for the different presentations of chronic GvHD.
Methods—Biopsy specimens of diseased and normal skin were obtained from patients presenting with lichen planus-like and sclerodermatous type chronic GvHD. Expression of epidermal cytokines, adhesion molecules and lymphoid surface markers was analysed by means of immunohistochemistry. Apoptosis was detected using the in situ nick endlabelling method.
Results—In both GvHD lesion types, CD8+ cells predominated in the epidermis, whereas CD4+ cells were the most prevalentin the dermis. Apoptotickeratinocytes were found in diseased skin only and Fas antibodies labelled a considerable number of keratinocytes. The epidermis in both types of lesions expressed interleukin (IL) 1α, tumour necrosis factor (TNF) α and intercellular adhesion molecule (ICAM)-1, but dermal vascular cell adhesion molecule (VCAM)-1 expression was restricted to specimens of lichen planus-like GvHD. IL1α and E-selectin were expressed in normal looking skin of 55% and 80%, respectively, of patients with lichen planus-like GvHD.
Conclusion—The similarity between expression of epidermal cytokines and adhesion molecules (with the exception of VCAM-1) and lymphocyte phenotype in lichen planus-like and sclerodermatous GvHD strongly suggests that the latter occurs as a consequence of the healing process. VCAM-1 distinguishes between lichen planus-like and sclerodermatous lesions. IL1α and E-selectin are potential early markers of chronic GvHD.
Keywords: graft versus host disease
Keywords: skin
Keywords: lymphocytes cytokines
Keywords: adhesion molecules
Full text
PDF






Images in this article
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Adams D. H., Shaw S. Leucocyte-endothelial interactions and regulation of leucocyte migration. Lancet. 1994 Apr 2;343(8901):831–836. doi: 10.1016/s0140-6736(94)92029-x. [DOI] [PubMed] [Google Scholar]
- Anasetti C., Rybka W., Sullivan K. M., Banaji M., Slichter S. J. Graft-v-host disease is associated with autoimmune-like thrombocytopenia. Blood. 1989 Mar;73(4):1054–1058. [PubMed] [Google Scholar]
- Atkinson K., Horowitz M. M., Gale R. P., van Bekkum D. W., Gluckman E., Good R. A., Jacobsen N., Kolb H. J., Rimm A. A., Ringdén O. Risk factors for chronic graft-versus-host disease after HLA-identical sibling bone marrow transplantation. Blood. 1990 Jun 15;75(12):2459–2464. [PubMed] [Google Scholar]
- Atkinson K., Munro V., Vasak E., Biggs J. Mononuclear cell subpopulations in the skin defined by monoclonal antibodies after HLA-identical sibling marrow transplantation. Br J Dermatol. 1986 Feb;114(2):145–160. doi: 10.1111/j.1365-2133.1986.tb02793.x. [DOI] [PubMed] [Google Scholar]
- Bailey A. J., Bazin S., Delaunay A. Changes in the nature of the collagen during development and resorption of granulatin tissue. Biochim Biophys Acta. 1973 Dec 6;328(2):383–390. doi: 10.1016/0005-2795(73)90272-9. [DOI] [PubMed] [Google Scholar]
- Barker J. N., Mitra R. S., Griffiths C. E., Dixit V. M., Nickoloff B. J. Keratinocytes as initiators of inflammation. Lancet. 1991 Jan 26;337(8735):211–214. doi: 10.1016/0140-6736(91)92168-2. [DOI] [PubMed] [Google Scholar]
- Bevilacqua M. P. Endothelial-leukocyte adhesion molecules. Annu Rev Immunol. 1993;11:767–804. doi: 10.1146/annurev.iy.11.040193.004003. [DOI] [PubMed] [Google Scholar]
- Bos J. D., Kapsenberg M. L. The skin immune system: progress in cutaneous biology. Immunol Today. 1993 Feb;14(2):75–78. doi: 10.1016/0167-5699(93)90062-P. [DOI] [PubMed] [Google Scholar]
- Chosidow O., Bagot M., Vernant J. P., Roujeau J. C., Cordonnier C., Kuentz M., Wechsler J., André C., Touraine R., Revuz J. Sclerodermatous chronic graft-versus-host disease. Analysis of seven cases. J Am Acad Dermatol. 1992 Jan;26(1):49–55. doi: 10.1016/0190-9622(92)70005-z. [DOI] [PubMed] [Google Scholar]
- Dustin M. L., Singer K. H., Tuck D. T., Springer T. A. Adhesion of T lymphoblasts to epidermal keratinocytes is regulated by interferon gamma and is mediated by intercellular adhesion molecule 1 (ICAM-1). J Exp Med. 1988 Apr 1;167(4):1323–1340. doi: 10.1084/jem.167.4.1323. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gaschet J., Mahé B., Milpied N., Devilder M. C., Dréno B., Bignon J. D., Davodeau F., Hallet M. M., Bonneville M., Vié H. Specificity of T cells invading the skin during acute graft-vs.-host disease after semiallogeneic bone marrow transplantation. J Clin Invest. 1993 Jan;91(1):12–20. doi: 10.1172/JCI116160. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gavrieli Y., Sherman Y., Ben-Sasson S. A. Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol. 1992 Nov;119(3):493–501. doi: 10.1083/jcb.119.3.493. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Goulmy E., Gratama J. W., Blokland E., Zwaan F. E., van Rood J. J. A minor transplantation antigen detected by MHC-restricted cytotoxic T lymphocytes during graft-versus-host disease. Nature. 1983 Mar 10;302(5904):159–161. doi: 10.1038/302159a0. [DOI] [PubMed] [Google Scholar]
- Groves R. W., Ross E. L., Barker J. N., MacDonald D. M. Vascular cell adhesion molecule-1: expression in normal and diseased skin and regulation in vivo by interferon gamma. J Am Acad Dermatol. 1993 Jul;29(1):67–72. doi: 10.1016/0190-9622(93)70154-l. [DOI] [PubMed] [Google Scholar]
- Hogan D., Card R. T., Ghadially R., McSheffrey J. B., Lane P. Human immunodeficiency virus infection and porphyria cutanea tarda. J Am Acad Dermatol. 1989 Jan;20(1):17–20. doi: 10.1016/s0190-9622(89)70002-5. [DOI] [PubMed] [Google Scholar]
- Janin-Mercier A., Devergie A., Van Cauwenberge D., Saurat J. H., Bourges M., Lapiere C. M., Gluckman E. Immunohistologic and ultrastructural study of the sclerotic skin in chronic graft-versus-host disease in man. Am J Pathol. 1984 May;115(2):296–306. [PMC free article] [PubMed] [Google Scholar]
- Kasten-Sportès C., Masset M., Varrin F., Devergie A., Gluckman E. Phenotype and function of T lymphocytes infiltrating the skin during graft-versus-host disease following allogeneic bone marrow transplantation. Transplantation. 1989 Apr;47(4):621–624. doi: 10.1097/00007890-198904000-00012. [DOI] [PubMed] [Google Scholar]
- Koch A. E., Kronfeld-Harrington L. B., Szekanecz Z., Cho M. M., Haines G. K., Harlow L. A., Strieter R. M., Kunkel S. L., Massa M. C., Barr W. G. In situ expression of cytokines and cellular adhesion molecules in the skin of patients with systemic sclerosis. Their role in early and late disease. Pathobiology. 1993;61(5-6):239–246. doi: 10.1159/000163802. [DOI] [PubMed] [Google Scholar]
- Kägi D., Ledermann B., Bürki K., Seiler P., Odermatt B., Olsen K. J., Podack E. R., Zinkernagel R. M., Hengartner H. Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice. Nature. 1994 May 5;369(6475):31–37. doi: 10.1038/369031a0. [DOI] [PubMed] [Google Scholar]
- Murphy G. F., Lavker R. M., Whitaker D., Korngold R. Cytotoxic folliculitis in GvHD. Evidence of follicular stem cell injury and recovery. J Cutan Pathol. 1991 Oct;18(5):309–314. doi: 10.1111/j.1600-0560.1991.tb01541.x. [DOI] [PubMed] [Google Scholar]
- Norton J., Sloane J. P. A prospective study of cellular and immunologic changes in skin of allogeneic bone marrow recipients. Relationship to clinical and histologic features of acute graft-versus-host disease. Am J Clin Pathol. 1994 May;101(5):597–602. doi: 10.1093/ajcp/101.5.597. [DOI] [PubMed] [Google Scholar]
- Norton J., Sloane J. P. ICAM-1 expression on epidermal keratinocytes in cutaneous graft-versus-host disease. Transplantation. 1991 Jun;51(6):1203–1206. doi: 10.1097/00007890-199106000-00011. [DOI] [PubMed] [Google Scholar]
- Norton J., Sloane J. P., al-Saffar N., Haskard D. O. Vessel associated adhesion molecules in normal skin and acute graft-versus-host disease. J Clin Pathol. 1991 Jul;44(7):586–591. doi: 10.1136/jcp.44.7.586. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Parkman R. Clonal analysis of murine graft-vs-host disease. I. Phenotypic and functional analysis of T lymphocyte clones. J Immunol. 1986 May 15;136(10):3543–3548. [PubMed] [Google Scholar]
- Parkman R. Graft-versus-host disease. Annu Rev Med. 1991;42:189–197. doi: 10.1146/annurev.me.42.020191.001201. [DOI] [PubMed] [Google Scholar]
- Piguet P. F., Grau G. E., Allet B., Vassalli P. Tumor necrosis factor/cachectin is an effector of skin and gut lesions of the acute phase of graft-vs.-host disease. J Exp Med. 1987 Nov 1;166(5):1280–1289. doi: 10.1084/jem.166.5.1280. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rochat A., Kobayashi K., Barrandon Y. Location of stem cells of human hair follicles by clonal analysis. Cell. 1994 Mar 25;76(6):1063–1073. doi: 10.1016/0092-8674(94)90383-2. [DOI] [PubMed] [Google Scholar]
- Rouvier E., Luciani M. F., Golstein P. Fas involvement in Ca(2+)-independent T cell-mediated cytotoxicity. J Exp Med. 1993 Jan 1;177(1):195–200. doi: 10.1084/jem.177.1.195. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rowbottom A. W., Norton J., Riches P. G., Hobbs J. R., Powles R. L., Sloane J. P. Cytokine gene expression in skin and lymphoid organs in graft versus host disease. J Clin Pathol. 1993 Apr;46(4):341–345. doi: 10.1136/jcp.46.4.341. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sayama K., Yonehara S., Watanabe Y., Miki Y. Expression of Fas antigen on keratinocytes in vivo and induction of apoptosis in cultured keratinocytes. J Invest Dermatol. 1994 Sep;103(3):330–334. doi: 10.1111/1523-1747.ep12394858. [DOI] [PubMed] [Google Scholar]
- Schattenfroh N. C., Hoffman R. A., McCarthy S. A., Simmons R. L. Phenotypic analysis of donor cells infiltrating the small intestinal epithelium and spleen during graft-versus-host disease. Transplantation. 1995 Jan 27;59(2):268–273. [PubMed] [Google Scholar]
- Shulman H. M., Sale G. E., Lerner K. G., Barker E. A., Weiden P. L., Sullivan K., Gallucci B., Thomas E. D., Storb R. Chronic cutaneous graft-versus-host disease in man. Am J Pathol. 1978 Jun;91(3):545–570. [PMC free article] [PubMed] [Google Scholar]
- Sollberg S., Peltonen J., Uitto J., Jimenez S. A. Elevated expression of beta 1 and beta 2 integrins, intercellular adhesion molecule 1, and endothelial leukocyte adhesion molecule 1 in the skin of patients with systemic sclerosis of recent onset. Arthritis Rheum. 1992 Mar;35(3):290–298. doi: 10.1002/art.1780350307. [DOI] [PubMed] [Google Scholar]
- Sullivan K. M., Shulman H. M., Storb R., Weiden P. L., Witherspoon R. P., McDonald G. B., Schubert M. M., Atkinson K., Thomas E. D. Chronic graft-versus-host disease in 52 patients: adverse natural course and successful treatment with combination immunosuppression. Blood. 1981 Feb;57(2):267–276. [PubMed] [Google Scholar]
- Swerlick R. A., Lee K. H., Li L. J., Sepp N. T., Caughman S. W., Lawley T. J. Regulation of vascular cell adhesion molecule 1 on human dermal microvascular endothelial cells. J Immunol. 1992 Jul 15;149(2):698–705. [PubMed] [Google Scholar]
- Takata M. Immunohistochemical identification of perforin-positive cytotoxic lymphocytes in graft-versus-host disease. Am J Clin Pathol. 1995 Mar;103(3):324–329. doi: 10.1093/ajcp/103.3.324. [DOI] [PubMed] [Google Scholar]
- Thornhill M. H., Kyan-Aung U., Haskard D. O. IL-4 increases human endothelial cell adhesiveness for T cells but not for neutrophils. J Immunol. 1990 Apr 15;144(8):3060–3065. [PubMed] [Google Scholar]
- Tsoi M. S., Storb R., Dobbs S., Medill L., Thomas E. D. Cell-mediated immunity to non-HLA antigens of the host by donor lymphocytes in patients with chronic graft-vs-host disease. J Immunol. 1980 Nov;125(5):2258–2262. [PubMed] [Google Scholar]
- Ushiyama C., Hirano T., Miyajima H., Okumura K., Ovary Z., Hashimoto H. Anti-IL-4 antibody prevents graft-versus-host disease in mice after bone marrow transplantation. The IgE allotype is an important marker of graft-versus-host disease. J Immunol. 1995 Mar 15;154(6):2687–2696. [PubMed] [Google Scholar]








