Toward an Integrated View of Operational Tolerance in Human Renal Transplantation: A Systems Biology Perspective.

Operational tolerance (OT) is the phenomenon occurring in human renal and liver transplantation in which the body does not reject the organ after discontinuing immunosuppression for at least a year. We revisited the data generated by The Brazilian Multicenter Study on Operational Tolerance involving different conceptual fields - antigen-specific cytokine response, immune cell numbers and repertoire, signaling pathways, and epigenetics. We integrated our data to pave the way to systems biology thinking and harness debate on potential mechanisms in OT. We present original data on systems biology in OT, connecting potential mechanistic players. Using bioinformatics, we identified three dominant features that discriminate OT from its opposing clinical outcome, chronic rejection (CR). The OT-CR discriminative molecules were FOXP3, GATA3 and STAT6, each corresponding to a differential profile: (1) In FOXP3, OT presents preserved regulatory T cell (Treg) numbers but decreased numbers in CR; (2) in GATA3, increased expression is seen in OT; and (3) in STAT6, decreased monocyte activation is seen in OT. With these variables, we built molecular networks to identify interactions related to OT versus CR. Our first systems biology endeavor gave rise to novel potentially relevant interconnected players in OT mechanisms: FOXP3 connecting to interleukin-9 (IL-9) and IL-35 signaling, suggesting their immunoregulatory involvement in OT. Likewise, GATA3/FOXP3 interactions incrementing/stabilizing FOXP3 transcription suggest participation in keeping healthy FOXP3+ Tregs in OT. We envision that systems biology thinking will greatly contribute to advancing knowledge in human transplantation tolerance in an interactive perspective.

Regulatory/inflammatory cellular response discrimination in operational tolerance.

BACKGROUND: Antigen-specific cellular response is essential in immune tolerance. We tested whether antigen-specific cellular response is differentially modulated in operational tolerance (OT) in renal transplantation with respect to critical antigenic challenges in allotransplantation-donor antigens, pathogenic antigens and self-antigens. METHODS: We analysed the profile of immunoregulatory (REG) and pro-inflammatory (INFLAMMA) cytokines for the antigen-specific response directed to these three antigen groups, by Luminex. RESULTS: We showed that, in contrast to chronic rejection and healthy individuals, OT gives rise to an immunoregulatory deviation in the cellular response to donor human leucocyte antigen DR isotype peptides, while preserving the pro-inflammatory response to pathogenic peptides. Cellular autoreactivity to the N6 heat shock protein 60 (Hsp60) peptide also showed a REG profile in OT, increasing IL4, IL-5, IL-10 and IL-13. CONCLUSIONS: The REG shift of donor indirect alloreactivity in OT, with inhibition of interleukin (IL)-1B, IL-8, IL-12, IL-17, granulocyte colony-stimulating factor, Interferon-γ and monocyte chemoattractant protein-1, indicates that this may be an important mechanism in OT. In addition, the differential REG profile of cellular response to the Hsp60 peptide in OT suggests that REG autoimmunity may also play a role in human transplantation tolerance. Despite cross-reactivity of antigen-specific T cell responses, a systemic functional antigen-specific discrimination takes place in OT.

Influence of environmental patterns on the population structure and secondary production of the fiddler crab Uca maracoani (Latreille) in the Amazon mangroves.

Uca maracoani is a fiddler crab found in estuaries along the western Atlantic coast, with a notable preference for euhaline environments. This study aimed to analyze the population structure and dynamics of this species in an estuary on the North Coast of Brazil, specifically in an area of the upper estuary where seasonal rainfall fluctuations result in significant changes in salinity. Monthly crab samples were taken from December 2013 to November 2015, together with measurements of environmental variables, such as water and climate parameters. The population maintains a balanced sex ratio; however, males are generally larger, with lower mortality rates and longer lifespans than females. Reproduction is continuous but mainly takes place in the dry season when salinity levels are higher (above 12‰). Higher crab densities have been observed during the rainy season when, despite lower salinity levels (below 10‰), the conditions for survival (food availability and milder climate) seem to be more favorable. The estimated average annual biomass and production for the population were 2.62 g AFDM m-2 and 5.43 g AFDM m-2 year-1, respectively, characterized by a high turnover rate (P/B = 2.10 year-1). Our results suggest that U. maracoani has thriving populations in the Amazon coast's mangroves, benefiting from the vast muddy intertidal zone and the high organic content delivered by the estuaries.