The role of obesity in experimental skin transplant rejection

Author(s)

Fernanda Fernandes Terra

• Document type: Master's Dissertation
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI)
• Defense date: 2019-08-09

Examining board members

Niels Olsen Saraiva Câmara; José Carlos Farias Alves Filho; Denise Morais da Fonseca; Alexandre de Castro Keller

• Advisor: Niels Olsen Saraiva Câmara; Rafael Ribeiro Almeida

Abstract

Obesity is a public health problem in Brazil, it is associated with multiple increased comorbidities in recent decades and it also promotes chronic low-grade inflammation. For this reason, it is believed that obese patients are more likely to need some transplant throughout life. However, the contribution of obesity in organ transplant rejection remains contentious. Graft rejection persists as the major complication to transplanted patients. Then, we hypothesized that obesity accelerates graft rejection through modulating allogeneic response by favouring a proinflammatory profile. Thus, our aim was to evaluate the impact of obesity in allogeneic transplant rejection. We have induced obesity feeding male C57BL/6 mice with a high-fat diet (DH) for 12 weeks. We demonstrated that DH animals had superior weight gain compared to standard diet (DP), in addition to developing glucose intolerance. To evaluate the effect of diet-induced obesity on alloimmunity, we transferred the tail skin from male F1 (C57BL/6 x Balb/c, H-2b/d) or C57BL/6 (H-2b) mice to the back of DH and DP recipients. DH mice rejected semi-allogeneic skin grafts faster than DP, without interfering in syngeneic transplantation. This early rejection was accompanied by increased il-17a mRNA expression in the draining lymph nodes, as well as increased production of IL-17A by CD4&#43 T cells with no difference in IFN-g production. Graft rejection in obese mice was also correlated with a reduction in CD4&#43CD25&#43FoxP3&#43 T cells in the draining lymph nodes and an increase in dendritic cells activation when compared to DP mice. Considering the role of the microbiota as a potential modulator of the immune system and alloimmune responses, we evaluated its contribution in the context of transplant rejection. Treatment of lean mice with broad-spectrum antibiotics prior to transplantation reduced graft survival only when donor and recipient were treated. The mechanisms underlying this phenomenon need further investigation. However, treatment of obese mice was able to delay allogeneic rejection over untreated obese subjects. Graft rejection delay in antibiotic-treated obese mice was followed by a contraction on TH17 response. Thus, these results indicate that obesity has a negative impact on the outcome of the transplantation and this can be at least partially due to the obesity-related dysbiosis. (AU)

• FAPESP's process: 17/03248-4 - The role of obesity-related intestinal microbiota in experimental allogeneic skin transplantation
• Grantee: Fernanda Fernandes Terra
• Support Opportunities: Scholarships in Brazil - Master