Agrawal, Hemant:

The role of dendritic cells in the sepsis-induced immunosuppression

Duisburg, Essen (2006), 92 Bl.
Dissertation / Fach: Biologie; Medizin
Medizinische Fakultät » Universitätsklinikum Essen » Klinik für Unfallchirurgie
Schade, Fritz Ulrich (Doktorvater, Betreuerin)
Dissertation
Abstract:
The present study comprises of two parts. The first part deals with studies on the role of DCs during polymicrobial sepsis and the second part includes the exploitation of BMDCs as therapeutic agents to prevent the sepsis-induced immunosuppression. The data obtained from the first part indicated that the sepsis induced altered phenotypic and functional changes in the splenic and the lymph node DCs. There was marked maturation of DCs in the spleen and in the lymph nodes but this process of maturation occurred later in lymph nodes than in the spleen. The splenic DCs developed an altered cytokine secretion pattern, which was associated with the inability of splenic DCs to produce Th1-type cytokines such as IL-12 but released high levels of IL-10. This impairment of IL-12 synthesis was independent from endogenously produced IL-10 as neutralization of IL-10 did not restore the IL-12 secretion by DCs. But IFN-g treatment restored in part the IL-12 production by splenic DCs only during early sepsis. In addition, the splenic CD4+CD8- and CD4-CD8+ subpopulations were lost during sepsis, and the remaining DCs showed a reduced capacity for allogeneic T cell activation associated with decreased IL-2 synthesis. Thus, during sepsis DCs acquire a phenotype that might favor the development of Th2 and/or Treg cells and might inhibit effective immunity against the bacterial infection through Th1 cell polarization. The data obtained from the second part highlighted that the administration of competent BMDCs into septic mice changed the cytokine milieu in the spleen, representing a main secondary lymphoid organ situated near to the site of infection. The instillation of competent BMDCs resulted in the diminished loss of splenocytes and in reduced IL-10 production by these cells. The diminished loss of splenocytes was associated with an increased total T cell number in the spleen. In addition to the reduced IL-10 production by splenocytes mediated by the administration of BMDCs, a reduced secretion of TNF-a and IFN-g was also observed. Moreover, the reduced IL-10 production by splenocytes was not dependent on the IL-12 secreted by injected BMDCs. These changes in the spleen cytokine environment might favor the development of a Th1 response, which is required for the effective immunity against the bacterial infection. The present findings reinforce the idea that DCs are affected by sepsis and their replacement has some potentially beneficial contributions to the host’s response to infectious challenge. The present data are also in accord with an emerging understanding of the critical role played by DCs in the development of the proper Th1/Th2 cytokine balance during sepsis syndrome in order to ward off the invading bacteria. Thus, these data suggest that DCs are critical cells at the boundary between the innate and adaptive immune response and play an important role in bacterial responses.

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