Acceleration of apoptosis in CD4+CD8+ thymocytes by rapamycin accompanied by increased CD4+CD25+ T cells in the periphery.
BACKGROUND
Rapamycin (Rapa) is an immunosuppressant that is used in patients and animal models to control allograft rejection. Its mechanisms of action are not fully understood. In this article, the authors have investigated the effects of therapeutic doses of Rapa on both thymic and peripheral T-cell populations in the adult rat.


METHODS
The therapeutic dosage of Rapa was optimized using cardiac transplantation between LEW and DA rats. Thymic morphology was assessed by hematoxylin-eosin staining. Flow cytometric analysis was performed to analyze T-cell phenotype and apoptosis. T-cell receptor (TCR)-mediated T-cell responsiveness was evaluated by 3[H]-thymidine deoxyribose incorporation.


RESULTS
Rapa induced atrophy in the thymus but not in peripheral lymphoid organs. Moreover, fibrosis occurred in thymus that was long-lasting after Rapa withdrawal. In animals treated with Rapa, there was a significant reduction in CD4+CD8+ thymocytes caused by accelerated apoptosis, whereas CD4-CD8-, CD4+CD8-, and CD8+CD4- populations remained unaffected. In contrast, the cellularity of the periphery lymphoid organs was not altered. Within the CD4+ thymocyte population, CD4+CD25+ thymocytes were resistant to Rapa-accelerated apoptosis, and in the periphery, the ratio of CD4+CD25+ to CD4+CD25- T cells was increased. Notably, the peripheral CD4+CD25+ T cells were hyporesponsive to TCR-mediated activation.


CONCLUSIONS
The resistance of the peripheral CD4+CD25+ T cells to Rapa treatment might contribute to its immunosuppressive action. The long-term effects of Rapa on thymus atrophy and thymocyte development requires consideration with respect to its clinical application.
Tian
Lina
L
Division of Paediatric Surgery, Department of Surgery, University of Hong Kong Medical Centre, Queen Mary Hospital, Hong Kong SAR, People's Republic of China. ltian@hkucc.hku.hk
Lu
Liwei
L
Yuan
Zhengwei
Z
Lamb
Jonathan R
JR
Tam
Paul K H
PK
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D001284:Atrophy; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D023421:Models, Animal; D051381:Rats; D011917:Rats, Inbred Lew; D015375:Receptors, Interleukin-2 / Q000097:blood; D020123:Sirolimus / Q000494:pharmacology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D014184:Transplantation, Homologous / Q000276:immunology
D007166:Immunosuppressive Agents; D015375:Receptors, Interleukin-2; D020123:Sirolimus