Patient parameters and response after administration of rituximab in pediatric mature B-cell non-Hodgkin lymphoma.

BACKGROUND: Mature aggressive B-cell lymphomas are heterogenous malignancies that make up more than half of all diagnosed non-Hodgkin lymphoma in children and adolescents. The overall survival rate increased over the last decades to 80%-90% due to fine tuning of polychemotherapy. However, new therapeutic implications are needed to further increase the overall survival. Current clinical trials analyze the therapeutic effect of rituximab in pediatric patients, while the mechanism of action in vivo is still not fully understood. METHODS: Effector molecules important for tumor defense were analyzed before and at day 5 after rituximab treatment via flow cytometry. Serum rituximab levels were measured with an ELISA. RESULTS: We evaluated patient parameters that may affect treatment response in relation to rituximab administration and serum rituximab levels. We indeed found a reduction of Fcγ receptor (FcγR) II levels after rituximab treatment in monocyte subtypes, whereas FcγRI expression was significantly increased. Serum levels of proinflammatory marker proteins S100A8/A9 and S100A12 significantly decreased after treatment to normal levels from an overall proinflammatory state before treatment. CD57, perforin, and granzyme B expression decreased after treatment, comprising a less cytolytic natural killer (NK) cell population. CONCLUSION: The highlighted effects of rituximab treatment on patient's immune response help in understanding the biology behind tumor defense mechanisms and effector function. After subsequent studies, these novel insights might be translated into patient care and could contribute to improve treatment of pediatric patients with mature aggressive B-cell lymphoma.

Idiotype-specific CD4+CD25+ T suppressor cells prevent, by limiting antibody diversity, the occurrence of anti-dextran antibodies crossreacting with histone H3.

CD25(+) suppressor T cells regulate the immune response against the type-2 "thymus independent" bacterial polysaccharide antigen alpha(1-->3)dextran (Dex) in BALB/c mice. These T cells, represented by the clone 178-4 Ts, restrict the Dex-specific IgG antibody repertoire such that the J558 idiotype dominates. Antibodies with other structures in the heavy-chain variable region (V(H) region), predominantly within the CDR3 domain, occur when the T cell control fails. This increase of antibody diversity caused by a lack of CD25(+) Ts cells, e.g. in nude mice, does not result in the appearance of antibodies with enhanced affinity to the antigen Dex, but often leads to a crossreactivity with autologous proteins. Twenty-two out of sixty Dex-specific hybridomas from nude mice, but no hybridomas from euthymic mice, crossreact with a nuclear protein, as tested by ELISA. This nuclear protein was identified as histone H3. Ten of the sixty hybridomas from nude mice were sequenced and show V(H) sequences that deviate from the original J558 sequence. Three of these ten hybridomas crossreact with the histone H3. Adoptive transfer of CD25(+) Ts cells to nude mice leads to a marked increase of antibodies carrying the original J558 idiotype within the IgG pool after immunization with Dex. Our data demonstrate a CD25(+) Ts cell-mediated restriction of V(H) usage, which prevents the appearance of crossreactive autoantibodies.