Roland Kurrle

T Cell Activation by CD3 Antibodies

Monoclonal antibodies which recognize the T3 antigen on human T cells have turned out to be excellent tools for analyzing T cell activation. The T3 antigen complex seems to be involved in specific immune functions, either as a receptor or as molecules functionally or physically associated with the receptor (1–3). In contrast to T cell activation by mitogens, the activation via anti-T3 antibodies seems to reflect antigen-specific lymphocyte stimulation. It is well established that mere binding of different anti-T3 antibodies triggers mitogenesis (4,5), induces the production of immune mediators like interferon (γ-IFN) and interleukin-2 (IL-2) (6–8), and blocks cytotoxic effector functions and antigen-specific proliferative responses (9). However, to date all studies of the activation of human T cells via the T3 antigen complex have been carried out with monoclonal antibodies of the IgG2a isotype (OKT3) or the IgG1 isotype (Leu-4, UCHT1). From the functional point of view the isotypes of anti-T3 antibodies seem to play a critical role in the efficiency and the mechanism of T cell activation. Whereas anti-T3 antibodies of the IgG2a isotype are highly effective in activating T cells from all donors by an IL2-dependent mechanism (8,10), for anti-T3 antibodies of IgG1 isotype nonresponsiveness caused by polymorphism in the accessory cell function has been described (11). Based on blocking experiments with Fc fragments of normal IgG (12,13) and analysis of different ethnic groups, the cause of nonresponsiveness seems to be genetic variations of the Fc-γ receptor of accessory cells (11,14).

The influence of aclacinomycin a on the immune response and on experimental immune disorders

The anti-cancer drug Aclacinomycin A (ACM) was able to inhibit the humoral immune response of mice against sheep red blood cells. This could be demonstrated in the formation of antibody secreting cells (PFC) and serum antibody titers, when ACM was administered either together with the antigen or three days after antigen application. Cellular immunity was not affected by the drug. In two murine Graft-vs-Host (GvH) disease models leading to two different B cell dependent auto-immune diseases (immune complex glomerulonephritis and immune hemolytic anemia) a protective effect of ACM was observed when it was administered at the time of the graft. The application of ACM in the induction phase mitigated the development of glomerulonephritis and prevented animals from dying due to hemolytic anemia. Only a slight therapeutical effect was observed when ACM was given after the appearance of clinical symptoms. In a T cell induced auto-immune disease (experimental allergic encephalomyelitis (EAE], ACM had no discernible effect on the course of the disease. It seems that the therapeutic effects of ACM on GvH-diseases are mediated via suppression of B-lymphocytes.

Regulation of alloreactivity in the popliteal lymph node assay by the new immunosuppressants: malononitrilamides

Abstract Malononitrilamides (MNAs) represent a new class of low molecular weight immunosuppressants and have been shown to prevent and reverse ongoing acute allograft rejection and effectively prolong xenograft survival in rodents. MNAs were also found to be potent inhibitors of B and T cell‐mediated autoimmune processes and mediate their effects by binding specifically to dihydr‐orotate dehydrogenase (DHODH), inhibiting de novo pyrimidine biosynthesis, thereby blocking T and B cell proliferation and strongly suppressing the IgM and IgG antibody production. Here we evaluated the effects of the MNAs (HMR 1279 and HMR 1715) on the in vivo lymphoproliferation that occurs after challenge with allogeneic cells in a local graft‐versushost reaction in Lewis × Brown Norway F1 hybrid rats by measuring the enlargement of the popliteal lymph nodes (PLN) draining the site of allogeneic cell injection. Oral administration of the MNAs dose‐dependently prevented the localized lymphoproliferative response in the PLN assay and suppressed the lymph node hyperplasia. The MNAs even acted therapeutically when they were given during an ongoing alloreactivity as late as days 4 or 5 after challenge. Consistent with the mode of action, a complete reversal of the immunosuppression on the lymphoproliferation in vivo was attempted in this protocol by the addition of exogenous uridine during days 0–5. These data suggest the HMR 1279 and HMR 1715 mediate their antiproliferative and immunosuppressive effects in the PLN assay in vivo by decreasing the activity of DHODH in the lymph node cells and thereby inhibiting pyrimidinebiosynthesis.