Modulation of Regulatory T Cells by Human IL-18
a technology il18, which is applied in the field of human il18 modulation of regulatory t cells, can solve the problems of bone marrow cell suppression, neurotoxicity, and inability to use following vaccination, and achieve the effects of increasing the number of systemic cd8+ effector t-cells, decreasing the number of systemic treg cells, and decreasing the number of intratumoral treg cells
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experimental example 1
IL-18 Treatment of Tumor-Bearing Mice
[0134]β2-microglobulinnull / NOD / scid mice were injected subcutaneously with a lung adenocarcinoma cell line (L55). After tumors were established (100-200 mm3), the mice were injected intraperitoneally with 50×106 human peripheral blood mononuclear cells (PBMCs), followed by a three week course of daily subcutaneous (s.c.) injections of 0.75 mg / kg recombinant human IL-18 (rhIL-18) in 6 mice and mock-rhIL-18 treatment in 4 mice. Tumor volumes were monitored, and upon sacrifice (24 hours after the final rhIL-18 injection), the intratumoral distribution and number of human T cell subsets was determined by immunohistochemistry. Paraffin sections from the tumor were reacted with an antibody specific for human CD45 (FIG. 1, left panel), human CD8 (FIG. 1, middle panel), or human CD4 (FIG. 1, right panel).
[0135]As shown in FIG. 1, the overall level of human CD45+ cell engraftment was increased (left panel) in IL-18 treated mice (black bars), compared to m...
experimental example 2
IL-18 Treatment of Non-Tumor-Bearing Mice
[0138]β2-microglobulinnull / NOD / scid mice (n=6) were injected intraperitoneally (i.p.) with 50×106 human PBMCs, followed by a three week course of daily subcutaneous injection of 0.75 mg / kg rhIL-18. IL-18 injections began 24 hours after the PBMC injection. After the three week course of IL-18 injections, the animals were sacrificed. Peripheral blood and fluid from the peritoneal cavity were obtained and processed for flow cytometry. In addition, the liver and the spleen were isolated from the animals. Portions of the organs were fixed, embedded in paraffin, and sectioned for immunohistochemical analysis. The remainder of the organs were processed for flow cytometry. Antibodies specific for human CD45, CD4, CD8, CD25, or FoxP3 were used in both immunohistochemical and flow cytometric analyses. In some experiments, the distribution of cells of human origin in other organs, including the lungs, kidney, skin and bone marrow was examined.
[0139]FIG....
experimental example 3
IL-18 Treatment of Non-Tumor-Bearing Mice Injected with PBMCs or PBLs
[0142]β2-microglobulin− / − / NOD / scid mice were injected intraperitoneally with 50×106 human PBMCs or 30×106 human peripheral blood lymphocytes (PBLs), followed by a three week course of daily subcutaneous (s.c.) injections of 0.75 mg / kg rhIL-18. After the three week course of IL-18, the animals were sacrificed. The spleen was isolated from each animal, fixed, embedded in paraffin and sectioned for immunohistochemical analysis. Paraffin sections from the spleen were reacted with antibodies specific for human FoxP3 or human CD8.
[0143]The results are depicted in FIG. 5. A statistically-significant decrease in Tregs occurs both with injection of PBMCs and of PBLs (left graph). However, a statistically-significant increase in CD8+T cells occurs only with the injection of PBMCs (right graph). Therefore, the results demonstrate that the IL-18-mediated increase in CD8+ T cells is dependent on the presence of monocyte / macroph...
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