During tumor growth there are a series of phenotypic and functional changes that occur in macrophages (M<sub>Φ</sub>) that ultimately lead to the immunosuppression of the tumor-bearing host (TBH). To investigate the phenotypic changes of M<sub>Φ</sub> during tumor growth, we examined the expression of the M<sub>Φ</sub> surface antigens, Mac-1, Mac-2, Mac-3, and Ia on peritoneal and splenic M<sub>Φ</sub>. In the peritoneal cavity there was no change in the percentage of Mac-1⁺ M<sub>Φ</sub> but a decrease in the percentage of Mac-2⁺, -3⁺, and Ia⁺ M<sub>Φ</sub> during tumor growth. In addition, three distinctly sized populations of peritoneal M<sub>Φ</sub>, showing differential antigen expression, also shifted during tumor growth. In the peritoneal cavity there was a decrease in the percentage of M<sub>Φ</sub> co-expressing the Mac-2, -3, and Ia antigens, leading to a shift towards Mac-1⁺ 2⁻ 3⁻ Ia⁻ TBH M<sub>Φ</sub>. In splenic M<sub>Φ</sub>, the percentage of Mac-1⁺, -2⁺, and -3⁺ M<sub>Φ</sub> increased, while the percentage of Ia⁺ M<sub>Φ</sub> decreased. Splenic M<sub>Φ</sub> showed an increase in the percentage of M<sub>Φ</sub> co-expressing Mac-1, -2, and -3 antigens and a decrease in the percentage of M<sub>Φ</sub> co-expressing Ia, leading to a shift towards a Mac-1⁺ 2⁺ 3⁺ Ia⁻ TBH M<sub>Φ</sub>. Taken together, these data suggest that tumor growth alters the phenotype of M<sub>Φ</sub> and causes a shift in M<sub>Φ</sub> subpopulations.
After measuring the phenotypic changes in M<sub>Φ</sub> during tumor growth, changes in M<sub>Φ</sub> accessory function to T cells were assessed. TBH M<sub>Φ</sub> have significantly reduced accessory activity for autoreactive T cells. This reduction is caused by decreased Ia antigen expression and increased production of the suppressor molecule, prostaglandin (PG). TBH M<sub>Φ</sub> down-regulated autoreactive T cell responsiveness to interleukin (IL)-1, IL-2, and IL-4. In addition to TBH M<sub>Φ</sub> reducing T cell responsiveness to cytokines, TBH CD4⁺ T cells alone were less responsive to the cytokines IL-1, IL-2, and IL-4. To examine the responsiveness of M<sub>Φ</sub> to activation signals, lipopolysaccharide (LPS) was incubated with normal and TBH splenic M<sub>Φ</sub> and assessed for their phenotypic, functional, and cell-cycle changes. The data showed that TBH M<sub>Φ</sub> had a decreased responsiveness to LPS.
We showed that there was a shift from an Ia⁺ M<sub>Φ</sub> in the normal host to an Ia⁻ M<sub>Φ</sub> in the TBH. Concomitant with the shift in TBH M<sub>Φ</sub> Ia⁻ phenotype was a change in TBH M<sub>Φ</sub> function. Normal and TBH Ia⁻ M<sub>Φ</sub> were suppressor M<sub>Φ</sub>. TBH Ia⁻ M<sub>Φ</sub>, however, suppressed autoreactive and alloreactive CD4⁺ T cells significantly more than could their normal counterparts. Tumor growth causes quantitative and qualitative changes in Ia⁻ suppressor M<sub>Φ</sub>. Although Ia⁻ M<sub>Φ</sub>-mediated suppression seemed to be the major source of down-regulation of CD4⁺ T cells, CD8⁺ T cells were not without fault. In the TBH, there was an increase in the percentage of CD8⁺ T cells and an increase in CD8⁺ T cell-mediated suppression. In conclusion, tumor growth leads to a change in immunoregulation that causes suppression of the immune response. / Ph. D.
| Identifer | oai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/38779 |
| Date | 12 July 2007 |
| Creators | Yurochko, Andrew David |
| Contributors | Microbiology and Immunology, Elgert, Klaus |
| Publisher | Virginia Tech |
| Source Sets | Virginia Tech Theses and Dissertation |
| Language | English |
| Detected Language | English |
| Type | Dissertation, Text |
| Format | xv, 231 leaves, BTD, application/pdf, application/pdf |
| Rights | In Copyright, http://rightsstatements.org/vocab/InC/1.0/ |
| Relation | OCLC# 23460054, LD5655.V856_1990.Y876.pdf |
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