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Verônica Coelho

Transplantation Response and Its Regulation

Some open questions

Verônica Coelho

Allogeneic organ transplantation induces a dramatic activation of the immune system in such a way that recipients have to be submitted to continuous immunosuppressive therapy in order to maintain the graft. And despite conventional immunosuppression, both acute and chronic rejections still occur. This intense immune stimulation is triggered by T cells which have the capacity of recognising polymorphic peptides presented by donor cells - Direct Allorecognition - or peptides derived from these molecules and presented by recipients´s antigen presenting cells Indirect Allorecognition (Figure 1). These molecules are mainly MHC molecules but also other polymorphic minor antigens trigger response. The intensity of this response is thought to be due to the high frequency of alloreactive T cells in the normal T cell repertoire, probably due to molecular mimicry between self and allo MHC molecules, after thymic selection (Figure 2). Therefore, the development of T cell repertoires generates both self and allo recognition in a common epigenetic process.

Figure 1
Figure 1

Looking at the immune system as a complex network of interactions, and based on several lines of evidence that T cell repertoires display intense physiological crossreactivity, we favour that other T cell repertoires are also activated in transplantation and may have important roles both in amplifying inflammation and in down regulating this process.

Figure 2
Figure 2

Accordingly, we have found higher T cell autoreactivity to autologous PBMC after transplantation than before transplantation, in renal transplant patients, indicating that the autoreactive T cell repertoire is modified after transplantation (Portugal et al., International Immunology, June 2001). In a recent sequential work, we also found that proliferation to human Heat Shock Protein 60 (Hsp60) was significantly associated with renal rejection in the first months after transplantation, while the Hsp60-induced IL-4 production was associated with absence of rejection. Moreover, we detected the predominance of an IL-4 dependent Hsp60-reactive population in the later period posttransplantation, possibly with regulatory function (manuscript in preparation). Collectively, these data suggest the coexistence of distinct anti-Hsp autoreactive T cell populations one proinflammatory, possibly predominant early posttransplantation and another with regulatory function and predominant in a later period.

Figure 3
Figure 3

Understanding the role of these autoreactive T cells in transplantation can contribute to identify possible antigens and or contexts that may be used to stimulate the activity of regulatory T cell repertoires, which may allow the system to re-establish another context of stability and tolerate the graft.

 

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