Je. Tanner et C. Alfieri, INTERACTIONS INVOLVING CYCLOSPORINE-A, INTERLEUKIN-6, AND EPSTEIN-BARR-VIRUS LEAD TO THE PROMOTION OF B-CELL LYMPHOPROLIFERATIVE DISEASE, Leukemia & lymphoma, 21(5-6), 1996, pp. 379-390
Post-transplant patients undergoing prolonged Cyclosporine A (CsA) imm
unosuppressive therapy were reported to have an increased incidence of
Epstein-Barr virus (EBV)-associated lymphoproliferative disorders. EB
V-infected B cells cultured with CsA demonstrated increased EBV B-cell
out-growth as compared to those cultured without CsA. Peripheral bloo
d mononuclear cells (PBMC), following infection with EBV and CsA treat
ment, demonstrated increased IL-6 activity in the culture supernatant.
The induction of IL-6 appeared to differ within the various lymphocyt
e populations. In monocytes and B cells, IL-6 expression was preferent
ially induced by EBV, and initiated by the binding of the two major vi
rion glycoproteins, gp350 and gp220, to CD21, or a CD21-like receptor.
Expression of IL-6 in T cells appeared to be due mainly to CsA. B cel
ls also expressed IL-6 following EBV exposure, but not following CsA t
reatment. EBV-immortalized B-cell lines cultured with CsA exhibited bo
th an increased number of cells expressing viral lytic-cycle antigens
and increased amounts of lytic-cycle proteins. IL-6, which was induced
by CsA in PBMC, was also capable of inducing the lytic viral cycle in
several EBV-immortalized cells. When IL-6 was expressed, it was shown
to act as an autocrine growth factor for B cells and to inhibit the i
mmune system allowing for the promotion of B-cell tumors by impairing
lymphokine-activated killer cells. Thus CsA treatment, in promoting bo
th increased numbers of lytic EBV B cells and expression of the EBV pa
racrine growth factor, IL-6, within the microenvironment of EBV B:T ce
ll and EBV B:monocyte interactions, may lead to increased EBV B-cell i
mmortalization and ultimately result in the promotion of B-cell lympho
mas in immunosuppressed patients.