DIFFERENTIAL-EFFECTS OF X-IRRADIATION AND CYCLOSPORINE-A ADMINISTRATION ON THE THYMUS WITH RESPECT TO THE GENERATION OF CYCLOSPORINE-A-INDUCED AUTOIMMUNITY
Ljj. Beijleveld et al., DIFFERENTIAL-EFFECTS OF X-IRRADIATION AND CYCLOSPORINE-A ADMINISTRATION ON THE THYMUS WITH RESPECT TO THE GENERATION OF CYCLOSPORINE-A-INDUCED AUTOIMMUNITY, Developmental immunology, 4(2), 1995, pp. 127-138
Cyclosporin A (CsA), a potent inhibitor of T-cell activation, has been
shown to have several effects on thymocyte maturation, thymic stromal
cells, and the generation of autoreactive T cells. In Lewis rats, the
combination of lethal irradiation, syngeneic bone marrow transplantat
ion, and a 4-week course of CsA administration causes the development
of an autoimmune disease (CsA-AI) resembling allogeneic graft-versus-h
ost disease. This occurs upon withdrawal of CsA, provided the thymus r
eceives irradiation and is present during CsA treatment. In this study
, the separate effects of irradiation or CsA treatment on thymic strom
al cells and thymocytes, compared to the combinatory effects, were exa
mined using immunohistochemistry and tricolor flow cytometric analysis
. CsA treatment causes an involution of the thymic medulla and a stron
g reduction of the cell number of thymocytes and stromal cells residin
g in the medulla. However, within the remaining medullary area, change
s in cell distribution and antigen density on these cells were not obs
erved. Irradiation on the other hand causes a strong depletion of thym
ocytes. The thymocyte population is recovered within 2 weeks and a cor
tical and medullary region can be distinguished. CsA treatment in comb
ination with irradiation results in a strongly inhibited recovery of t
he medulla during CsA treatment, whereas the cortex recovers to normal
size and morphology. The presence of the medullary IDC and epithelial
cells is reduced proportionally to the small size of the medulla. How
ever, the distribution of these stromal cells is normal. During the Cs
A administration, the thymuses from irradiated and CsA-treated rats ar
e very similar to thymuses from CsA-treated rats. In conclusion, no ch
anges specific for irradiation plus CsA treatment have been observed.
Regarding the distribution and size of medullary stromal cells and res
iding thymocytes, thymuses from irradiated and CsA-treated rats hardly
differ from the thymuses from rats treated only with CsA. Therefore,
irradiation seems essential in the generation of CsA-AI by eliminating
suppressor-cell circuits in the periphery.