Impact of 15-deoxyspergualin on effector cells in experimental autoimmune diseases of the nervous system in the Lewis rat

Abstract

SUMMARYThe influence of the immunosuppressivc antibiotic agent 15-deoxyspergualin (DSG) on macrophages and autoreactive T helper lymphocytes from Lewis rats was analysed in vitro and in vivo. DSG did not inhibit antigen-or mitogen-induced proliferation of encephalitogenic or neuritogenic T helper cell lines in vitro. However, the presence of DSG during in vitro activation of the T cells strongly suppressed or completely abrogated their capacity to induce encephalitis (EAE) or neuritis (EAN) after adoptive transfer to naive rats, although expression of activation markers or adhesion molecules on the T line blasts was not down-regulated by DSG, Like activationinduced T cell proliferation, IL-2-dependent growth of CD4^ T line cells was not affected by DSG, Preincubation of CD4^ T line cells in DSG during IL-2-driven proliferation for 48 h, however, inhibited the subsequent antigen-but not mitogen-induced activation of these T cells, although neither density of T eel) receptors nor other surface molecules involved in antigen recognition were lowered on the cells exposed to DSG. Similar to its effect in vitro, in vivo administration of DSG for 10 days even at a concentration with cumulative toxicity did not suppress in vitro proliferation of spleen cells induced by mitogen or a mitogenic combination of anti-CD2 antibodies. Furthermore, spleen cell and peripheral blood lymphocyte (PBL) surface antigens, particularly MHC molecules, were not altered by long-term treatment with DSG for 30 days. While there was a slight reduction in the number of polymorphonuclear cells in both populations, the proportion of the different leucocyte subpopulations remained unchanged. In contrast to the strong functional impact of DSG on autoreactive T helper cells, the drug did not inhibit the oxidative burst of macrophages or their MHC antigen expression. This study demonstrates a clear inhibitory effect of DSG on CD4''' T lymphocytes, but not macrophages. It provides an explanation for recent observations of a strong immunosuppressive in vivo effect of DSG on transplantation rejection and experimental autoimmune diseases, despite a normal mitogen response of T cells exposed to DSG in vivo and in vitro.

Macrophages in T cell line-mediated, demyelinating, and chronic relapsing experimental autoimmune encephalomyelitis in Lewis rats

“…T cell-EAE. An MBP-specific T cell line was derived from the popliteal lymph nodes of a Lewis rat immunized with guinea pig MBP in Freund's complete adjuvant (FCA) into the hind foot pad 10 days before, and established as described for a P2-specific T eell line [14]. Before transfer T line cells were activated as follows: 3 x 10 /ml T cells were incubated with 15 X 10^/ml freshly isolated irradiated (30Gy) syngeneie thymocytes as antigen-presenting cells in the presence of guinea pig MBP (20/ig/ml).…”

“…Therefore, the previously reported suppression of A-EAE after macrophage depletion might also be due to interference with peripherally located macrophages which presumably have an initiating role in antigen processing and presentation to T cells, rather than to interference with macrophages as effector cells in the CNS. To bypass this problem we now depleted macrophages during EAE induced by myeiin basic protein (MBP)-specific T cells (T cell-EAE) [14].…”

In vivoeffects of cyclic administration of 15-deoxyspergualin on leucocyte function in patients with Wegener's granulomatosis

“…DSG binds to chaperone proteins required for nuclear translocation of the transcription factor NF kappa B, thereby preventing cell activation. Because T cell proliferation and B cell maturation [5,6] are highly dependent upon nuclear translocation of NF kappa B, DSG gained much interest as a new immunosuppressive agent for the treatment of transplant rejection [7] and autoimmunity [8].…”