Helper Innate Lymphoid Cells (hILC) resist Immunosuppressive Therapy: an Observation from Kidney and Liver Transplantation

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Abstract

Introduction

We have previously observed that CD3+ CD8+ lymphocytes are depleted in the graft epithelium of intestinal transplant recipients who receive immunosuppressive therapy, while innate lymphoid cells type 1 and 3 (ILC1 and ILC3) persist in high proportions. In this study we compare the ILC representation and its subsets (ILC1, including NK and non-cytotoxic helper ILC1 cells (hILC1), ILC2 and ILC3) in peripheral blood of kidney and liver transplanted recipients versus control subjects (CS) in order to identify possible frequency variations in the context of immune alloresponse and immunosuppressive therapy (IT).

Materials and Methods

Peripheral blood mononuclear cells (PBMCs) were obtained at day +14, from 88 kidney recipients (KTR14): 11 received only triple therapy (No-I), 46 received induction therapy with thymoglobulin (I-TMG) and 31 with Basiliximab (I-Bas), from 19 liver recipients (LTR14): 16 were No-I and 3 I-Bas) and from 48 CS. Total ILC were identified by flow cytometry as CD45+ Lin- (CD3, CD19, CD14) and its subsets were defined as: ILC1 (CD117-CRTH2-), ILC2 (CD117-CRTH2+) and ILC3 (CD117+ CRTH2-). ILC1 were subdivided in NK and hILC1 according to CD127 and CD94.

Results and Discussion

• ILC2 and ILC3 are higher in KRT14 vs CS (p<0.0001 and p=0.0002, respectively) whereas ILC1 (NK and hILC1) are lower (p<0.0001) (Figure 1A). These differences in ILC subsets frequencies are due to decreasing of ILC1 absolute number (Figure 1B) whereas ILC2 and ILC3 numbers are not statistically different between KRT14 and CS. Similar results were obtained from the liver cohort (Figure 1C (p<0.0001 for ILC1 and ILC2, p=0.0005 for ILC3)) and 1D (p<0.0001)).

Results and Discussion

• hILC1 frequency is higher (p=0.0001) whereas NK frequency is lower (p=0.0001) in KRT14 vs CS and LTR14 vs CS (p=0.0002 and p=0.008, respectively). These differences in ILC1 subsets frequencies are due to decreasing of NK absolute number (p<0.0001) (Figure 2A) whereas hILC1 number (Figure 2B) is not statistically different between KRT14 vs CS and LTR14 vs CS (Figure 2C (p<0.0001) and Figure 2D).

Results and Discussion

• Decreasing of NK in KRT14 was mostly observed in patients who received TMG at pretransplant as induction therapy (Figure 3).

Results and Discussion

• The obtained results from comparing LTR14 vs CS are comparable to those observed between KTR14 vs CS. Due to the fact that most of LTR14 only received triple therapy it seems that it leads to NK but no ILC depletion.

Conclusion

hILC are unaffected by TMG and Basiliximab used as induction therapy for kidney and liver transplantation. hILC are also unaffected by tacrolimus-based triple therapy used as maintenance treatment.

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