The role of Th17:Treg balance in allograft rejection is incompletely understood and remains an active area of investigation. Prior studies have suggested that CD28 costimulation may downregulate Th17 but enhance nTreg development. In particular, the study of Th17 cells in alloimmunity has been greatly hampered by their paucity in vivo.
The ABMTbet-/- mouse model addresses several of these challenges. This mouse has a transgenic TCR with specificity for the bm12 antigen and is characterised by a greater than 10-fold increased level of Th17 cells at baseline with further increases after transplantation. Allograft rejection in this model is accelerated and the alloresponse is predominantly Th17 mediated (>2-fold increase in Th17 in dLN post transplantation). Using an ABMTbet-/- model, we evaluated the effect of CTLA4-Ig in modulating the alloresponse, when biased towards Th17 generation.
3 x 106 CD4+ T cells from ABMTbet-/- mice were IV injected into B6.Cg.Foxn1nu mice receiving bilateral bm12 skin transplants. Recipients were treated with CTLA4-Ig 500ug on D0, then 250ug on D2, D4 and D6. Spleens and draining lymph nodes were harvested at day 10.
Treatment with CTLA4-Ig resulted in a marked decrease in overall transgenic CD4+ in spleen and draining lymph nodes both in terms of percentage (spleen: 0.27±0.01% vs 1.44±0.06%, p<0.0001; dLN: 1.08±0.18% vs 2.39±0.15%, p<0.0001) and absolute numbers (spleen: 11.22±0.83×104 vs 107±3.96×104, p<0.0001; dLN: 16.4±1.11×103 vs 57.8±15.2×103, p<0.0001). CTLA4-Ig led to significant reductions in alloreactive Th17 cells (spleen: 6.2±0.36% vs 14.4±0.85%, p<0.0001; dLN: 8.04±0.91% vs 13.2±0.47%, p<0.001) and Foxp3+ Tregs (spleen: 1.88±0.14% vs 7.3±0.67%, p<0.0001; dLN: 1.3±0.15% vs 8.82±0.88%, p<0.0001). Th1 cells were non-significantly decreased. Overall, this effect led to a shift in the effector response towards a Th17 predominant phenotype with a marked increase in Th17/Treg (3.50±0.47 vs 1.86±0.12, p<0.05) ratio after treatment with CTLA4-Ig. In contrast, Th1/Treg ratio was not significantly altered (4.86±1.17 vs 2.65±0.73, p=0.22).
In summary, CTLA4-Ig markedly decreases overall allospecific T cell proliferation. However, in the absence of Th1, it results in a significant increase in Th17/Treg ratio. The impact of these effects on long-term allograft outcome warrants further investigation.
To cite this abstract in AMA style:McGrath M, Yeung M, Yang S, Zaman N, Snawder B, Najafian N. Effect of CTLA4-Ig on the Fate of Alloreactive Th17 Cells In Vivo, The [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/effect-of-ctla4-ig-on-the-fate-of-alloreactive-th17-cells-in-vivo-the/. Accessed October 28, 2020.
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