Regulatory T cells, IL-2 greatly reduced during pAIH treatment
Intrahepatic regulatory T cells (Tregs), enriched in untreated paediatric autoimmune hepatitis (pAIH) patients, are disproportionately reduced during treatment, a new study reveals. Similarly, serum concentrations of interleukin (IL)-2 also decrease during treatment.
“Until the start of this study there was no systematic analysis of intrahepatic Treg numbers available, neither before nor under ongoing therapy in pAIH,” said researchers. “Thus, we retrospectively immunophenotyped the intrahepatic T and B cell compartment, including Treg in pAIH in the initial diagnosis and in the follow-up during therapy.”
The infiltration density of CD4+ + CD8+ cells were significantly greater in untreated pAIH (3,373 cells/mm2) than in treated pAIH patients (2,065 cells/mm2; p=0.003). CD79+ cells were also significantly greater in untreated (1,135 cells/mm2) than in treated (710 cells/mm2; p=0.03) pAIH patients. [PLoS One 2017;doi:10.1371/journal.pone.0181107]
CD4+ FOXP3+ density (p<0.001), CD4+ FOXP3+ / CD79+ ratio (p=0.004) and CD4+ FOXP3+ / CD4+ + CD8+ ratio (p<0.001) were significantly reduced in treated than in untreated pAIH patients. Of these, portal levels of CD4+ FOXP3+ T-cells showed the largest decline (146 to 63 cells/mm2), resulting in a subsequent significant decline in CD4+ FOXP3+ to CD4+ and CD8+ ratio (0.044 to 0.021).
Declines in Treg levels during treatment may be explained in part by the steroid and azathioprine nature of immunosuppressive therapy, according to researchers. Another explanation may be the insufficient regulation of Tregs in the liver in response to the shortage of IL-2 during therapy.
“Additionally, chemokines like CXCL10 (IP-10) that are involved in Treg homing into the liver are significantly downregulated under ongoing therapy in pAIH. Thus, a reduced hepatic recruitment of Treg could contribute to the Treg decline under therapy as well,” researchers said.
A comparison of the concentrations of 28 serum cytokines between treated and untreated pAIH patients showed that 11 were significantly reduced during treatment. These were IL-2, IL-6, IL-8, IL-9, IL-15, IL-17, FGFβ, IP-10, MIP-1a, MIP-1b and HGF.
While most of these cytokines showed two- to fivefold reductions in serum levels, IL-2, which had the greatest decline during treatment, showed a reduction of around tenfold. Moreover, IL-2 levels were significantly higher in untreated pAIH patients than in untreated adult AIH (aAIH) patients (p<0.05).
“[T]he strong reduction of the serum IL-2 and 10 other cytokines observed here go simultaneously to a contraction of the intrahepatic T cell pool, the main intrahepatic IL-2 source, as expressed by declining T cell densities within the shrinking infiltrates under therapy in pAIH and aAIH. This may contribute to the disproportionate decline of intrahepatic Treg,” researchers explained.
The study included 53 paediatric patients (40 untreated, 13 under therapy) with confirmed AIH; 12 paediatric nonalcoholic fatty liver disease patients were included as liver histology controls, while 34 age- and gender-matched healthy paediatric controls were included for blood cytokine assessment.
“The disproportional decline of intrahepatic Treg during ongoing therapy is consistent in pAIH and aAIH and may result from a decrease of the Treg survival factor IL-2. Such associations are relevant for the design and evaluation of novel approaches for second line therapies or the withdrawal of the immunosuppressive therapies,” researchers concluded.