Hamann, Carina

English

Heart failure (HF) is often associated with inflammation and activation of the immune system. Moreover, the development to HF has been shown to be accompanied by autoimmune reactions since cardiac autoantibodies were identified in many studies. However, the role of T cells in load-induced HF had not been addressed previously. We hypothesized that an aortic constriction leading to hypertrophy and subsequently to HF can activate autoreactive T cells, which contribute to the progression of the disease. To examine autoimmune responses towards a cardiomyocyte-specific antigen, cMy-mOVA mice were used, which express ovalbumin (OVA) selectively on cardiomyocytes. In these mice, HF was induced by increasing the afterload by transverse aortic constriction (TAC). It was previously demonstrated in our group that cMy-mOVA mice did not show an accelerated impairment of heart function after TAC operation, although an activation of OVA-specific cytotoxic T lymphocytes (CTLs) was observed at a low level. To clarify the role of autoreactive T cells, TAC-operated cMy-mOVA mice were challenged by transfer of OVA-specific CD4+ and CD8+ T cells. The adoptive transfer of CD8+ and/or CD4+ did not significantly accelerate progression to HF. However, double-transgenic cMy-mOVA/OT-II mice, in which the majority of T cells are OVA-specific CD4+ T cells, showed an accelerated progression towards HF. Since these mice did not develop OVA-specific autoantibodies, we could demonstrate that CD4+ T cells with specificity for a cardiomyocyte-specific autoantigen can promote the progression from hypertrophy to HF independent of autoantibodies.
The immunological milieu within the myocard might not only affect the progression of HF but also the chances of repair by new regenerative therapies, e.g. the transplantation of stem cell-derived grafts. To clarify the probability of engraftment and reduce the risk of complications for the recipient after stem cell-derived graft transplantations, the immunogenicity of pluripotent stem cells (PSCs) and their differentiation products has to be considered. It is known that the mismatch of major histocompatibility complex (MHC) molecules lead to acute rejection of grafts but additionally, minor histocompatibility (miHC) antigens affect engraftment of organs even between MHC-matched individuals. Consequently, the role of miHC antigens in PSCs and their derivates need to be clarified since they cannot be matched in allogeneic transplantations. For this, OVA-expressing embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) were used to monitor immune responses against OVA as a model of a miHC antigen after injection into otherwise syngeneic mice. It was demonstrated that the expression of OVA led to a significantly reduced rate of engraftment of PSCs. OVA-specific CTLs and OVA-specific antibodies were observed in the hosts. Therefore, a single antigen can be sufficient to induce rejection of transplanted PSC-derived grafts suggesting that therapies using grafts derived from MHC-matched allogeneic PSCs will likely require immunosuppressive or immunomodulatory treatment.
Since PSCs are at risk to give rise to teratomas if residuals of pluripotent cells remain in a graft after in vitro differentiation, the susceptibility of PSCs to natural killer (NK) cells was analyzed. Previous antibody inhibition studies indicated that the killing of murine PSCs by NK cells was mainly mediated by the activating NK cell receptor NKG2D. To clarify the role of NKG2D for killing of murine PSCs, NKG2D-deficient and wildtype NK cells were analyzed concerning their potential to kill several PSC lines including multipotent adult germline stem cells (maGSCs), ESCs and iPSCs. Naïve NKG2D-deficient NK cells failed to kill PSCs. Stimulation of NK cells by interleukin-2 (IL-2) increased the killing but could not completely compensate the NKG2D deficiency. Hence, it was demonstrated that NKG2D is an important activating receptor involved in killing of murine PSCs.2017-07-2

Georg-August-University Göttingen

Investigation of immune responses contributing to the pathogenesis of load-induced heart failure and the rejection of stem cell grafts

https://ediss.uni-goettingen.de/bitstream/11858/00-1735-0000-0028-8811-6/1/Thesis%20Carina%20Hamann.pdf

Investigation of immune responses contributing to the pathogenesis of load-induced heart failure and the rejection of stem cell grafts

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Georg-August-University Göttingen