The probability of producing a specific antitumor response should be increased by multiplying the number of T lymphocytes that encounter the malignant cells. We tested this prediction in a murine model, using a recently discovered T-cell chemokine, lymphotactin (Lptn). This chemokine increased tumor cell infiltration with CD4+ lymphocytes but generated little antitumor activity. Coexpression of the T-cell growth factor interleukin-2, however, greatly expanded the T lymphocytes attracted by Lptn, affording protection from the growth of established tumor in a CD4+ and CD8+ T cell-dependent manner. Lesser synergy was seen with GM-CSF. Hence coexpression of a T-cell chemokine and T-cell growth factor potentiates antitumor responses in vivo, suggesting a general strategy to improve cancer immunotherapy.

Background: Rheumatoid factor (RF) is a characteristic but not pathognomic feature in patients with rheumatoid arthritis (RA). It is unknown whether the repertoire of immunoglobulin genes utilized by RF+ B cells of RA patients is unique and whether RF+ B cells in normal individuals are silenced or deleted. Materials and Methods: Clonal B cell populations were established from the peripheral blood of normal donors (127 B cell clones), RA patients (113 RF-and 60 RF+ B cell clones) and patients with primary Sjogren's syndrome (82 RF-and 47 RF+ B cell clones) by coculturing with anti-CD3-stimulated T helper cell clones. The cross-reactivity pattern of antibodies secreted by the B cell clones was determined by ELISA on a panel of antigens. The molecular structure of the IgM heavy chains was characterized by VH family-specific RT-PCR and sequencing. VH elements which correlated with RF specificity were identified. The responsiveness of B cells expressing these VH elements to T helper cell signals was compared in normal individuals and RA patients. Results: The majority of RF+ B cells were monospecific when specificity was tested on five antigens. RF+ B cells expressed a significantly different repertoire of VH gene Address correspondence and reprint requests to: C. M. Weyand, Mayo Clinic, 401 Gugg.,

In many different murine models, the immunogenicity of tumor cells can be increased by transduction with a range of immunostimulatory genes, inducing an immune response that causes regression of pre-existing unmodified tumor cells. To investigate the relevance of these animal models to pediatric malignancy, we used autologous unirradiated tumor cells transduced with an adenovirus-IL-2 to immunize 10 children with advanced neuroblastoma. In a dose-escalation study, we found that this tumor immunogen induced a moderate local inflammatory response consisting predominantly of CD4+ T lymphocytes, and a systemic response, with a rise in circulating CD25+and DR+ CD3+ T cells. Patients also made a specific antitumor response, manifest by an IgG antitumor antibody and increased cytotoxic T-cell killing of autologous tumor cells. Clinically, five patients had tumor responses after the tumor immunogen alone (one complete tumor response, one partial response, and three with stable disease). Four of these five patients were shown to have coexisting antitumor cytotoxic activity, as opposed to only one of the patients with nonresponsive disease. These results show a promising correlation between preclinical observations and clinical outcome in this disease, and support further exploration of the approach for malignant diseases of children. © 1998 by The American Society of Hematology.

T cell-dependent Ig production involves interaction between T cells and B cells. This study evaluated the effects of prostaglandin (PG) E(2) on Ig production in a system in which B cells were co-cultured with autologous CD4(+) T cell clones non-specifically activated by anti-CD3. The effects of PGE(2) on T cell-dependent Ig production differed substantially, depending on the T cells employed. We selected six T cell clones that were able to enhance Ig production (resistant T cell clones) and six T cell clones that inhibited Ig production in the presence of PGE(2) (sensitive T cell clones) for comparison. The resistant T cells produced high levels (>1000 pg/ml) of IL-2 and/or IL-4, and expressed high CD40L, OX40 and CD45RA, and low CD45RO. In contrast, sensitive T cells secreted low IL-2 (<500 pg/ml) and IL-4 (<200 pg/ml), and expressed low CD40, OX40 and CD45RA, and high CD45RO. Adding supernatant derived from resistant T cell clones restored Ig production inhibited by PGE(2), while removing IL-2, IL-4 or IL-10 using specific antibodies inhibited Ig production. In addition, we demonstrated a direct effect of PGE(2) on B cells to enhance Ig production. Consistently, in the presence of resistant T cells, PGE(2) increased B cell proliferation and differentiation. In conclusion, the effects of PGE(2) on Ig production consist of its indirect effects through T cells and its direct effects on B cells. The outcome of the effects can be up-regulatory or down-regulatory, depending whether resistant or sensitive T cells are involved.