The participation of the humoral immune system in rheumatoid arthritis (RA) is characterized by the production of rheumatoid factors (RF). RF are autoantibodies against the Fc part of IgG which are encoded by diverse germ-line genes. Most of the RF-encoding genes are unmutated, but in RA, a substantial quantity is encoded by somatically mutated genes. In addition, the synovial membranes (SM) of the diseased joints of RA patients are infiltrated by B lymphocytes which form germinal center-like aggregates. To analyze the local immune response, B cell foci from two RA SM were isolated by micromanipulation. From DNA of these foci, the rearranged kappa light chain variable region (V kappa) genes were amplified by polymerase chain reaction (PCR), cloned and sequenced. The amplification of different V kappa-J kappa combinations of different foci suggested oligoclonal expansion of B lymphocytes, which was confirmed by sequence analysis: each PCR product contained members of a single B cell clone. The sequence analysis of 29 different clones revealed rearrangements of diverse V kappa genes. Both frequent representatives of the V kappa 3 and the V kappa 1 family, as well as rarely used genes such as the L10 and B2 genes of the V kappa 2 and V kappa 5 families were found. Of the eleven potentially functional gene rearrangements, eight were significantly mutated, indicating their derivation from antigen-selected B cells. Intraclonal diversity in one of these clones may suggest ongoing mutation in the diseased synovial membrane of patients with RA.

Utilizing monoclonal reagents directed towards antigens of the monocyte-macrophage lineage and Ia antigens, the tissue architecture of synovial membranes obtained from patients with non-inflammatory joint diseases and patients with rheumatoid arthritis was studied. Emphasis was placed on the localization of the type I, type II and type III synoviocytes that previously had been defined by their cell surface phenotype with regard to the expression of monocyte-macrophage lineage (M theta) and Ia antigens as well as by their phagocytic capacity or the ability to produce glycosaminoglycans. In patients with non-inflammatory joint diseases, cells with the M theta + Ia+ (type I) phenotype constituted the majority of synoviocytes immediately adjacent to the joint cavity; cells with this phenotype were also scattered in the subsynovial tissue and in the perivascular regions. The fibroblastoid type III cells defined by the absence of both M theta and Ia antigens formed the major cell population in the subsynovial tissue in this patient group. In patients with rheumatoid arthritis, the Ia+ M theta + cells were present in a characteristic double configuration forming an intensely positive layer adjacent to the intra-articular space followed by an Ia- M theta - layer that again was succeeded by an intensely Ia+ M theta + layer. Large numbers of synoviocytes bearing M theta + Ia+ antigens were also demonstrated in the diffusely inflamed subsynovial tissue, in the perivascular regions as well as around and within lymphoid infiltrates.(ABSTRACT TRUNCATED AT 250 WORDS)

There is an obvious discrepancy between the popularity of mistletoe extracts and their classification as a non-conventional treatment modality with unproven efficacy in oncology. The commercial preparations suffer from several major drawbacks: lack of precise declarations for the molecular characteristics and the concentrations of diverse extract constituents; the composition of extracts can even be influenced by the different methods of preparation, the time of harvest, and the type of host tree; lack of experimentally substantiated instructions for the dose of supposedly effective substance(s) and the schedule of applications to clinically trigger an undisputably documented antitumoral activity; lack of thorough clinical studies according to the generally accepted criteria as the measure for responsible recommendations. To provide the indispensable set of data for a rational decision, the immunomodulatory galactosidespecific lectin was biochemically characterized and its antitumoral/antimetastatic activity was documented in three murine tumor model systems, occurring within a narrow dose range. Biweekly treatment with s.c. injections of a lectin dose of 1 ng/kg caused no notable harmful side-effects in patients, who showed modulation of selected immune parameters. In a group of 23 patients with advanced cancer no at least partial remission was seen. In principle, enhancement of factors like cytokine availability or NK-cell activity is not necessarily linked to therapeutic benefit. Factors such as growth promotion of certain tumor cell lines by cytokines, occurrence of respective insensitivity in advanced stages or varying levels of target sensitivity to cell-mediated cytotoxicity with significant interindividual differences deserve attention. Each tumor class has to be considered separately for its responsiveness. Similarly crucial for the decision of the focus of trials are valid suggestions for indicators to reliably recognize responders. Monitoring, for example, the presence of cytokine receptors or of MHC epitopes on tumor cells or the stimulation of the levels of acute-phase proteins in serum may be helpful. Taken together, this generally applicable course of research for a rigorously defined plant preparation or an isolated compound, culminating in the decisive clinical trials according to the approved criteria, will help answer the pertinent question on the oncological relevance of this treatment modality.

(7 Clin Pathol 1997;50:654-660)

Mononuclear cell (MNC) populations in tissue specimens from 11 colorectal adenocarcinomas and 1 mucinous adenocarcinoma were analyzed, applying different monoclonal antibodies (MoAB). Tumor epithelium could be characterized by MoAB VEP9, predominantly binding to mucus secreted by the tumor cells. In approximately 30%-50%, the tumor epithelium also reacted in a patchy pattern with the MoABs OKT10 and OKIa, which define in the peripheral blood activated and HLA-DR expressing cells. T-lymphocytes, as defined by the MoAB 9.6, and T-lymphocyte subpopulations, as characterized by the MoABs OKT4 and OKT8, were found in the intratumoral stroma and in peritumoral inflammatory areas. Quantifying the relative amounts of mononuclear cell subpopulations in the different stroma compartments, a predominance of OKT10- and OKIa-defined and MoAB-S39-reactive cells was observed. NK cells, as labelled by the MoAB Leu-7, were only demonstrated singularly in different areas of the stroma. Nonlymphoid structures such as vessel walls were shown to express antigens recognized by the MoABs OKIa, OKT10, and Leu-7. In some instances, nerve structures were labelled by the MoABs OKIa, OKT10, S39, and Leu-7. Using semiquantitative analysis, no correlation could be obtained between the intratumoral and peritumoral infiltration with T-lymphocytes, T-lymphocyte subpopulations and monocytic cells, and histopathological tumor grading and staging.