Further understanding of the nature of the cell of origin in FL has been provided by analysis of the immunoglobulin variableregion gene sequences of the tumor cells. During differentiation, normal B lymphocytes undergo a series of recombinatorial and mutational changes in their immunoglobulin variable-region genes. The V(D)J rearrangements of V H and V L genes occur mainly in the bone marrow, and, after encounter with antigen, the somatic mutation mechanism is activated in centroblasts in the GC. [1][2][3] In this site, certain mutated sequences are selected by antigens held on follicular dendritic cells, leading to affinity maturation of the antibody response. Survival, maturation, and subsequent fate of selected B cells are directed by several additional elements in the GC, including CD40L ϩ T cells and cytokine milieu. [1][2][3] For FL, it is clear that the cell of origin has undergone somatic mutation and that in many patients this process has continued after transformation, leading to intraclonal variation of V gene sequences. [4][5][6] This behavior is consistent with location in the GC. Because normal B cells rely on engagement of the B-cell receptor for activation of the mutation mechanism, the finding of continuing mutational activity has led to debate about the role of antigens in stimulating FL. 7 However, it appears that ongoing mutational activity may be limited in FL, 8 but it is not apparent in cases that have transformed to diffuse lymphoma after chemotherapy. 5,9 Uncertainty about the role of antigen in FL also cannot easily be resolved by analysis of mutational patterns in V genes because it is now evident that there is a natural tendency of the complementaritydetermining region (CDR) sequences to accumulate replacement mutations. 10 It remains unclear, therefore, whether antigen has a role in influencing the behavior of tumor cells in FL.However, the importance of immunoglobulin expression in FL is highlighted by the fact that in most patients with FL, expression is retained, in spite of the fact that one allele of chromosome 14 is commonly disrupted at 14q32 by the t(14;18) translocation. 11,12 Consequent overexpression of bcl-2 protein by the nonfunctional immunoglobulin allele is one mechanism that contributes to tumor cell survival. The almost universal conservation of immunoglobulin expression by the remaining functional allele might indicate a selective advantage for tumor cells in FL. The question arises as to whether this is dependent on stimulation by antigen.Immunoglobulin carries N-glycosylated oligosaccharides located mainly in the heavy-chain constant regions. These act as spacers for the immunoglobulin molecule that are important for For personal use only. on May 11, 2018. by guest www.bloodjournal.org From maintaining effector functions. 13 Because of locations of the sites in the interstitial region between the C H 2 domains, the oligosaccharide chains are incompletely galactosylated and sialylated. 14 Human antibodies do not generally contain O-linked oligosaccharides, wi...

Vaccination with idiotypic protein protects against B-cell lymphoma, mainly through anti-idiotypic antibody. For use in patients, DNA vaccines containing single-chain Fv derived from tumor provide a convenient alternative vaccine delivery system. However, single-chain Fv sequence alone induces low anti-idiotypic response and poor protection against lymphoma. Fusion of the gene encoding fragment C of tetanus toxin to single-chain Fv substantially promotes the anti-idiotypic response and induces strong protection against B-cell lymphoma. The same fusion design also induces protective immunity against a surface Ig-negative myeloma. These findings indicate that fusion to a pathogen sequence allows a tumor antigen to engage diverse immune mechanisms that suppress growth. This fusion design has the added advantage of overcoming potential tolerance to tumor that may exist in patients.

This study was designed to assess the safety and efficacy of human umbilical cord mesenchymal stem cells (UC-MSCs) in the treatment of rheumatoid arthritis (RA). In this ongoing cohort, 172 patients with active RA who had inadequate responses to traditional medication were enrolled. Patients were divided into two groups for different treatment: disease-modifying anti-rheumatic drugs (DMARDs) plus medium without UC-MSCs, or DMARDs plus UC-MSCs group (4×10(7) cells per time) via intravenous injection. Adverse events and the clinical information were recorded. Tests for serological markers to assess safety and disease activity were conducted. Serum levels of inflammatory chemokines/cytokines were measured, and lymphocyte subsets in peripheral blood were analyzed. No serious adverse effects were observed during or after infusion. The serum levels of tumor necrosis factor-alpha and interleukin-6 decreased after the first UC-MSCs treatment (P<0.05). The percentage of CD4(+)CD25(+)Foxp3(+) regulatory T cells of peripheral blood was increased (P<0.05). The treatment induced a significant remission of disease according to the American College of Rheumatology improvement criteria, the 28-joint disease activity score, and the Health Assessment Questionnaire. The therapeutic effects maintained for 3-6 months without continuous administration, correlating with the increased percentage of regulatory T cells of peripheral blood. Repeated infusion after this period can enhance the therapeutic efficacy. In comparison, there were no such benefits observed in control group of DMARDS plus medium without UC-MSCs. Thus, our data indicate that treatment with DMARDs plus UC-MSCs may provide safe, significant, and persistent clinical benefits for patients with active RA.

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