Cyclosporin A-induced changes of the thymic microenvironment. A review
of morphological studies
N.M. Milicevic and Z. Milicevic
Institute of Histology and Embryology, Faculty of Medicine,
University of Beograd, Beograd, Yugoslavia
Offprint requests to: Prof.
Dr. Novica Milicevic, Dim. Tucovi´ca 83, 11000 Beograd, Yugoslavia
Summary. Cyclosporin A is an
immunosuppressive drug, which disrupts the activation of peripheral T-lymphocyte
pool and blocks the maturation of thymo-cytes within the thymus. Normally,
thymic nonlymphoid cells provide the optimal inductive microenvironment
for development of T-lymphocytes. After application of cyclosporin A the
complex alterations of the thymic microenvironment occur, affecting all
types of nonlymphoid cells.
All subsets of thymic epithelial cells are thoroughly
changed. The subcapsular epithelial cells show the prominent enlargement
of cytokeratin contents. In electron microscopy, however, these cells present
the morpho-functional aspect of resting cells. The epithelial cells in deeper
cortex become enlarged and stockier, whereby their cell processes appear
more ramified and thicker. Thus, the cytoreticulum they create seems much
denser. These cells strongly express MHC antigens. Their subcellular organization
is suggestive of increased synthetic and secretory activity. The number
of medullary epithelial cells is decreased. The cells with the most mature
phenotype are the most prominently depleted and the ones with phenotypically
and morphologically immature appearance predominate.The number of Hassall's
bodies is also decreased.
The number of cortical macrophages does not increase.
However, these cells become enlarged showing the prominent changes in enzyme
capacity, histo-chemical features and ultrastructural organization. Thus,
they become similar to macrophages located in the cortico-medullary zone
of the normal rat thymus. Cortical macrophages increase the activity of
hydrolytic enzymes, acid phosphatase and nonspecific esterase, develop the
strong activity of chloroacetate esterase, the strong activity of respiratory
enzyme succinic dehydro-genase and begin to show the marked presence of
prostaglandin synthase. Moreover, the cytoplasmic inclusions, which are
aldehyde fuchsin- and PAS-positive and show sudanophilia, appear within
cortical macrophages. In electron microscopy these cells show an abundant
cytoplasm a very active appearance and the variety of vacuolar cytoplasmic
inclusions. The mitoses of neighboring thymocytes are often seen. The number
of interdigitating cells is decreased due to reduced size of thymic medulla,
but these cells do not show the substantial phenotypic changes.
The description and classification of all types of nonlymphoid
cells, which constitute the normal thymic microenvironment, is also presented.
The functional significance and possible mechanisms of CSA-induced changes
of the thymic microenvironment are discussed. Histol. Histopathol. 13,
1183-1196 (1998)
Key words: Thymus, Thymic microenvironment,
Thymic nonlymphoid cells, Cyclosporin A
DOI: 10.14670/HH-13.1183
|