Immunotherapeutic Implications Research Articles

IL-15 in the life and death of lymphocytes: immunotherapeutic implications

Interleukin (IL)-2 and IL-15 play contrasting roles in the life and death of lymphocytes. IL-2 favors the death of self-reactive lymphocytes to yield self-tolerance, whereas IL-15 favors the survival of memory CD8 + T cells. The actions of IL-15 on memory cell persistence and its inhibition of the immunological checkpoint, activation-induced cell death, enable the maintenance of long-lasting immune responses to vaccines. This supports our view that IL-15 should be used in lieu of IL-2 in the treatment of cancer and as a component of vaccines for cancer and AIDS. Furthermore, we suggest that IL-15 plays a major role in the pathogenesis of autoimmune diseases and propose that therapy involving monoclonal antibodies directed at the IL-15 receptor be evaluated in the treatment of such disorders.

Antibody penetration into living cells: pathogenic, preventive and immuno-therapeutic implications.

The dogmatic and at one time prevalent concept that intact antibody molecules were not able to enter into viable cells has now been modified due to the availability of a large amount of experimental findings and clinical observations that indicate otherwise. Penetration of mature autoantibodies into living cells might participate in the pathogenesis of diverse autoimmune diseases, through inducing apoptosis of healthy tissues and cells, but also by contributing to the breakdown of self-tolerance through presentation of self-antigens to the immune system. Conversely, the penetration of naturally occurring autoantibodies into immature lymphoid cells might have a physiological role in the edition of the immune repertoire in healthy individuals. Increasing interest is being paid to the potential immunotherapeutic role of penetrating antibodies as tools to deliver drugs, isotopes or genes into cells.

Induction of anti-tumor activity following autologous stem cell transplantation: immunotherapeutic implications

Induction of anti-tumor activity following autologous stem cell transplantation: immunotherapeutic implications

Autoantibody-associated cross-reactive idiotypes expressed at high frequency in chronic lymphocytic leukemia relative to B-cell lymphomas of follicular center cell origin

Using murine monoclonal antibodies (MoAbs) specific for immunoglobulin (Ig) cross-reactive idiotypes (CRI), we performed immunohistochemical analyses on frozen tissue sections and cytocentrifuge preparations of Ig-expressing malignant cells from patients with chronic lymphocytic leukemia (CLL) and B-cell non-Hodgkin's lymphomas (NHL) of follicular center cell origin. Twenty percent (4/20) of the Ig kappa light chain- expressing CLL cells reacted with 17.109, a MoAb against a major CRI on human IgM autoantibodies that is encoded by a conserved Ig variable- region gene (V gene) of the V kappa IIIb sub-subgroup. Another MoAb specific for V kappa IIIb framework determinant(s) reacted exclusively with all the 17.109-reactive CLL cells. Only one of 20 kappa light- chain-expressing CLL cells reacted with 6B6.6, a monoclonal antibody specific for a CRI commonly found on rheumatoid factor (RF) paraproteins with light-chain variable regions of the V kappa IIIa sub- subgroup. Finally, greater than 20% (8/34) of all CLL reacted with G6, a MoAb specific for an Ig heavy chain-associated CRI present on several RF paraproteins. In contrast, these CRIs were expressed at significantly lower frequencies in NHL of follicular center cell origin. Only one of 30 NHL expressing kappa light chains reacted with the 17.109 MoAb. Also, in contrast to the concordance between the 17.109-CRI and V kappa IIIb framework determinant(s) in CLL, two lymphomas in addition to the 17.109-reactive lymphoma were recognized by the anti-V kappa IIIb framework MoAb. None of the NHL reacted with either the 6B6.6 or the G6 MoAbs. These results are the first to demonstrate that CLL and NHL differ with respect to the expression of autoantibody-associated CRIs. The data support the notion that NHL of follicular center cell origin differs from CLL in its utilization and/or somatic mutation of Ig variable-region genes. The physiological and immunotherapeutic implications of these findings are discussed.

Autoantibody-Associated Cross-Reactive Idiotypes Expressed at High Frequency in Chronic Lymphocytic Leukemia Relative to B-Cell Lymphomas of Follicular Center Cell Origin

Using murine monoclonal antibodies (MoAbs) specific for immunoglobulin (Ig) cross-reactive idiotypes (CRI), we performed immunohistochemical analyses on frozen tissue sections and cytocentrifuge preparations of Ig-expressing malignant cells from patients with chronic lymphocytic leukemia (CLL) and B-cell non-Hodgkin's lymphomas (NHL) of follicular center cell origin. Twenty percent (4/20) of the Ig kappa light chain-expressing CLL cells reacted with 17.109, a MoAb against a major CRI on human IgM autoantibodies that is encoded by a conserved Ig variable-region gene (V gene) of the V kappa IIIb sub-subgroup. Another MoAb specific for V kappa IIIb framework determinant(s) reacted exclusively with all the 17.109-reactive CLL cells. Only one of 20 kappa light-chain-expressing CLL cells reacted with 6B6.6, a monoclonal antibody specific for a CRI commonly found on rheumatoid factor (RF) paraproteins with light-chain variable regions of the V kappa IIIa sub-subgroup. Finally, greater than 20% (8/34) of all CLL reacted with G6, a MoAb specific for an Ig heavy chain-associated CRI present on several RF paraproteins. In contrast, these CRIs were expressed at significantly lower frequencies in NHL of follicular center cell origin. Only one of 30 NHL expressing kappa light chains reacted with the 17.109 MoAb. Also, in contrast to the concordance between the 17.109-CRI and V kappa IIIb framework determinant(s) in CLL, two lymphomas in addition to the 17.109-reactive lymphoma were recognized by the anti-V kappa IIIb framework MoAb. None of the NHL reacted with either the 6B6.6 or the G6 MoAbs. These results are the first to demonstrate that CLL and NHL differ with respect to the expression of autoantibody-associated CRIs. The data support the notion that NHL of follicular center cell origin differs from CLL in its utilization and/or somatic mutation of Ig variable-region genes. The physiological and immunotherapeutic implications of these findings are discussed.

MHC class I gene expression by tumors: immunotherapeutic implications.

An anti-tumor role has been established for macrophages (Fidler 1974; Fernandez-Cruz et al. 1985), NK cells (Talmadge et al. 1980; Kawase et al. 1982), and helper T cells (Fugiwara et al. 1984; Greenberg et al. 1985) in various experimental systems, but an optimal immune defense against tumor cell growth in vivo depends on the ability of cytotoxic T lymphocytes (CTLs) to recognize and destroy malignant cells (Dailey et al. 1984; Rosenstein et al. 1984). This recognition involves an interaction between the effector cell and antigens present on the tumor cell in association with MHC class I molecules (Zinkernagel et al. 1979). The MHC class I molecules are composed of a heavy glycoprotein chain of 45 kilodaltons (kD) and a noncovalently-associated beta-2 microglobulin molecule of 15 kD (Hood et al. 1983). The heavy chain is highly polymorphic and is encoded by the H-2K, D and L loci in the mouse, and by the HLA-A, -B and -C loci in human. Virtually all normal cells display class I molecules (Daar et al. 1984), as do many tumor cells. Active immuno-surveillance in vivo may select for tumor variants with altered or down-regulated class I antigens, and reduced class I gene expression by tumors may provide a means of avoiding destruction by cytotoxic T lymphocytes.

Local Xenogeneic Graft-Vs-Host Reaction: A Practical Assessment of T Cell Function Among Cancer Patients

Abstract The local xenogeneic graft-vs-host reaction (XGVHR) was used as a practical bioassay to assess T lymphocyte function and immunocompetence among cancer patients. Positive XGVHR was found in 99.5% of normal donors, 70% of cancer patients with early stage disease, and 30% of cancer patients with metastatic disease (p < 0.001). A minimum of 4.5 × 106 immunocompetent T lymphocytes are necessary in order to elicit a positive XGVHR. Negative reactions among cancer patients are characterized by the lack of edema fluid accumulation and the appearance of the host basophils at the test site. This suggests that insufficient amounts of lymphokines are being released by the incompetent T lymphocytes, whereas the host is capable of mounting a rejection reaction as evidenced by the appearance of the basophils. Preliminary evidence suggests that the immunologic defect detected by the XGVHR cannot be corrected by monocyte depletion. The identification of putative suppressor T cell subsets may bear immunotherapeutic implications in the future.