Failure in peripheral immuno-surveillance due to thymic atrophy: importance of thymocyte maturation and apoptosis in adult tumor-bearer.
Tumor-induced immunosuppression often leads to failure in cancer therapy. Here, in an attempt to understand the course of tumor-dependent immunosuppression in young adult murine model, we found that in Ehrlich's ascites carcinoma (EAC) bearing mice, CD4(+) and CD8(+) populations of peripheral blood were depleted within first week of tumor inoculation. However, there was a rise in these populations at the end of second week only to fall back severely at the end of third week. These pulsating changes were also reflected in spleen. Interestingly, in thymus, production of CD4(+) and CD8(+) increased during first two weeks of tumor inoculation indicating the effort of thymus to replenish these populations in peripheral blood and spleen in response to their initial depletion, restricting tumor growth in between first and second weeks. However, at third week, due to (a) block in thymocyte maturation leading to increase in CD4(-)8(-) and decrease in CD4(+)8(+), (b) inhibition in formation of functional isotypes, and (c) thymocyte apoptosis, thymic reinforcement was stalled. Further investigation for the underlying mechanism of such thymic atrophy revealed down-regulation of anti-apoptotic protein Bcl-2 and up-regulation of pro-apoptotic protein Bax, resulting in decreased Bcl-2/Bax ratio thereby inducing apoptosis. Above findings accounted for the significant decrease in CD4(+) and CD8(+) of peripheral blood and spleen by the end of third week culminating in total collapse in the fight back mechanism of host and uncontrolled growth of tumor. All these results signify the importance of thymus in modulating the immune status of the host during tumor development.
Mandal
Debaprasad
D
Bose Institute, P-1/12 CIT Scheme VII M, Kolkata-700 054, India.
Bhattacharyya
Arindam
A
Lahiry
Lakshmishri
L
Choudhuri
Tathagata
T
Sa
Gaurisankar
G
Das
Tanya
T
D000818:Animals; D017304:Annexin A5 / Q000737:chemistry; D017209:Apoptosis / Q000502:physiology*; D001284:Atrophy; D016516:CD4-CD8 Ratio; D002286:Carcinoma, Ehrlich Tumor / Q000276:immunology*; D002453:Cell Cycle; D004247:DNA / Q000096:biosynthesis / Q000235:genetics; D005434:Flow Cytometry; D016650:Fluorescein-5-isothiocyanate; D005456:Fluorescent Dyes; D019254:Genes, bcl-2; D007157:Immunologic Surveillance / Q000502:physiology*; D008137:Longitudinal Studies; D051379:Mice; D009368:Neoplasm Transplantation; D019253:Proto-Oncogene Proteins c-bcl-2; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000502:physiology*; D013950:Thymus Gland / Q000276:immunology* / Q000473:pathology*; D051028:bcl-2-Associated X Protein
D017304:Annexin A5; C494827:Bax protein, mouse; D005456:Fluorescent Dyes; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D004247:DNA; D016650:Fluorescein-5-isothiocyanate