Abu-Elmagd, K

Nalesnik, M

Starzl, TE

Thomson, AW

PubMed

D-Scholarship@Pitt

-----------------------1.303 Influence of FK 506 on T Lymphocytes, Langerhans' Cells and the Expression of Cytokine Receptors and Adhesion Molecules in Psoriatic Skin Lesions: A Preliminary Study A.W. Thomson, M. Nalesnik, K. Abu-Elmagd, and T.E. Starzl PSORIASIS is a chronic dermatosis of presumed au-toimmune etiology 1 that is characterized by epider-mal hyperproliferation and by infiltration of the dermis. epidennis. and stratum corneum by lymphocytes and other inftammatory cells. Activated CD4 + T cells and secreted cytokines. including IFN- (which is elevated in psoriatic lesions) and interleukin-2 ClL-2). have been implicated in disease pathogenesis. Thus. T cells are found in close association with MHC class II+ (HLA-DR+) epidermal Langerhans' cells (candidate antigen presenting cells).2 Moreover. IFN- has been shown to induce the expression of HLA-DR and adhesion molecules (including intracellu-lar adhesion molecule I; ICAM-!) on vascular endothe-lium and epidermal keratinocytes.3 Increased expression of adhesion molecules on these cells promotes the binding of lymphocytes4 •s and may predispose both to the recruit-ment ofT cells into lesional tissue and to their activation.6 Cyclosporine A (CyA). an immunomodulatory drug used commonly to prevent graft rejection. inhibits CD4 + T-cell activation. cytokine gene expression. and cytokine production. It is highly effective in the treatment of psori-asis.7 We have shown previously that CyA markedly reduces the T-cell infiltrate within lesional skin. including numbers of IL-2 receptor+ (lL-2R+) cells. This effect is evident within 4 weeks of the start of therapy.s However. we also observed the persistence of adhesion molecule expression on lesional vascular endothelium despite reso-lution of the psoriatic plaques.9 FK 506 is a new immuno-suppressive agent with a similar mode of action to Cy A. 10 It has been shown to be highly effective in the prevention and treatment of organ transplant rejection and has been reported to exhibit fewer side effects than Cy A in trans-plant patients. II . 12 Its efficacy in psoriasis has been dem-onstrated recently in a preliminary study. 13 In this study we examined immunohistochemical changes within lesional skin of patients with severe recalcitrant psoriasis before and following the instigation of systemic FK 506 therapy. In view of our aforementioned observa-tions concerning Cy A. we were interested especially in the inftuence of FK 506 on T lymphocytes. epidermal Langer-hans' cells. IL-2R-bearing lymphocytes. and the expres-sion of adhesion molecules within lesional skin. MATERIALS AND METHODS Patients and Biopsies Elliptical or 3-mm punch biopsies were obtained under local xylocaine anesthesia from lesional skin of four female patients with severe chronic plaque psoriasis .. Tissue was obtained imme-diately before and 4 weeks after start of treatment with 0.15 mglkgld FK S06 (Fujisawa Pharmaceutical Co. Ltd.. Osaka. Japan) administered in oral gelatin capsules. Biopsies were mounted in OTC mounting medium (Fisher Scientific). snap-frozen in arctonlliquid nitrogen. and then stored at - 70·C before sectioning. Immunohistochemistry The method described by Horrocks et al9 was used. Six-micron cryostat sections were fixed in acetone for 20 minutes. air-dried. then incubated for I hour at room temperature with the appropri· ate. primary. mouse anti-human monoclonal antibody. These included CDI (Langerhans' cells), cm (mature T cells), CD4lT helper cells: Langerhans' cells). and CDS (T suppressor/cytotoxic cells), CD2S (a chain IL-2R; activated T cells). CDw60 {disease· associated T cells),14 HLA-DR and the adhesion molecules Calla~/1U (f37. integrin family), CD54 (lCAM·\), ELAM (endo-thelial leukocyte adhesion molecule), and VCAM (vascular cell adhesion molecule). Sections were incubated for 30 minutes with biotinylated polyclonal rabbit anti-mouse immunoglobulins (Dako). The color was developed using diaminobenzidine in buffered saline containing H20 2• RESULTS Clinical All patients showed marked improvement in their PASI (Psoriasis Area and Severity Index) score within 4 weeks of the start of FK 506 therapy. and histological examina-tion of lesional skin revealed a rapid decrease in inflam-matory cells and progressive loss of elongated rete pegs with the return of a normal stratum corneum. Immunophenotypic Analysis Examination of biopsies obtained during disease remission showed that, in comparison to pretreatment lesions. there were reductions in epidermal and dermal CD4 +, CD8+, CD25 + , and CDw60+ mononuclear cells (Fig l). In con-trast. there was a striking rise in COl + epidermal Langer-hans' cells. With respect to adhesion molecules, expres-sion of CD54 (ICAM-I) on residual lymphocytes and vascular endothelium persisted during FK 506-induced From the Departments of Surgery and Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania. Address reprint requests to A.W. Thomson, Division of Trans-plantation, Department of Surgery, Biomedical Science Tower, University of Pittsburgh, Pittsburgh, PA 15213. © 1991 by Appleton & Lange 0041-1345/91/$3.001+0 3330 Transplantation Proceedings, Vol 23, No 6 (December), 1991: pp 3330-3331 FK 506 ON PSORIATIC SKIN LESIONS Fig 1. Few residual IL·2R* (CD25+) mononuclear cells in the basal epidermis of lesional skin from a patient with severe psori-asis showing marked reduction in disease activity 4 weeks after the start of systemic FK 506 therapy. (x 100) disease remission. although staining became more re-stricted to the upper dermis. Staining for ELAM. which was observed in blood vessels throughout the dermis in active disease, was sitnilar or reduced in intensity in response to FK 506 treatment although there was disap-pearance of positive cells in the deeper dermis (Fig 2). Blood vessel staining for VCAM was focal and only faintly positive in active disease specimens, and there was evi-dence of persistent ~xpression during disease remission. DISCUSSION The findings of this preliminary immunohistochemical analysis of lesional skin from psoriasis patients treated with FK 506 are similar to those reported previously by several groups investigating the effects of systemic Cy A. Fig 2. Persistence of expression of the adhesion molecule ELAM on vascular endothelium within the dermis despite remission of psoriasis 4 weeks after the start of systemic FK 506 therapy. (X100) 3331 The reductions in overall T-cell numbers and in activated (lL-2R +) cells are consistent with the mode of action of FK 506. The significance of the increase in epidermal Langerhans' cells, which accompanied the diminution both in T-cell numbers and disease remission, remains to be elucidated. This early increase in Langerhans' cells upon instigation of therapy is not restricted to Cy A and FK 506, as treatment of psoriasis with retinoids, PUV A, or anthralin has also been shown to elevate COl + cell num-bers. IS Possible explanations have been discussed else-where. 16 In vitro studies of the influence of these Langer-hans' cells on lesional (CDw60+) T-cell function would prove informative. The persistence of CD54 and other adhesion molecule expression during FK 506-induced dis-ease remission suggests the likelihood of facilitated T-cell extravasation and disease recurrence following drug cur-tailment or withdrawal. as has been reported with Cy A and in two out of seven severe psoriasis patients treated thus far at the University of Pittsburgh Medical Center. Further in vitro studies are clearly required to further elucidate the in vivo action of FK 506 in psoriasis. ACKNOWLEDGMENTS We thank Drs Jegasothy. Ackerman. and Somach for providing biopsy material: Dr David Fox (Ann Arbor) for the gift of anti-CDw60; Dr Tim Springer (Boston) for anti-ICAM-I; Dr Nancy Hogg (London) for anti-COli. and Dr Walter Newman for anti-ELAM and anti-VCAM. REFERENCES I. Valdimarsson H. Baker BS. Jonsdottir I. et al: Immunol Today 7:256. 1986 2. Baker BS. Swain AF. Valdimarsson H. et al: Br J Dermatol 110:37. 1984 3. Griffiths CEM. Voorhees JJ. Nickoloff B1: J Am Acad DermatoI20:617. 1989 4. DustinML. Singer KH. Tuck DT. etal: J Exp Med 167:1323. 1988 5. Nickoloff B1: Arch Dermatol 124: 1835. 1988 6. Malegapuru WM. Sanders ME. Shaw S: Immunol Today 10:417. 1989 7. Ellis CN. Hamilton TA. Billings JK. et al: JAMA 256:3110. 1986 8. Horrocks C. Ormerod AD. Duncan n. et al: Clin Exp Immunol 78:166. 1989 9. Horrocks C. Duncan 11. Oliver AM. et al: Clin Exp Immunol 84:157, 1991 10. Thomson A W: Immunol Today 10:6. 1989 II. Starzl TE. Todo S. Fung J, et al: Lancet 2: 1000. 1989 12. Starzl TE. Todo S. Fung J. et al: Transplant Proc 22(suppl 1):5. 1990 13. Jegasothy B. Ackerman C. Fung J: Arch Dermatol (in press) 14. Baadsgaard O. et al: J Invest Dermatol 95:275. 1990 15. Czemielewski J. Juhlin L. Shroot S. et al: Acta Derm VenereoI65:97. 1985 16. Horrocks C. Duncan JI. Sewell HF: J Autoimmunity 3:559. 1990 

Influence of FK 506 on T lymphocytes, Langerhans' cells and the expression of cytokine receptors and adhesion molecules in psoriatic skin lesions: A preliminary study

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Influence of FK 506 on T lymphocytes, Langerhans cells and the expression of cytokine receptors and adhesions molecules in psoriatic skin lesions: A preliminary study

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Influence of FK 506 on T lymphocytes, Langerhans' cells and the expression of cytokine receptors and adhesion molecules in psoriatic skin lesions: A preliminary study

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