Compromised Immune Status in Post-Liver Transplant Patients with Biliary Complications

0
0
0

Compromised Immune Status in Post-Liver Transplant Patients with Biliary Complications

Introduction

Liver transplantation (LTx) is a life-saving procedure for many patients with end-stage liver disease. However, post-LTx complications, such as biliary complications (BC), can significantly impact patient outcomes. Immunosuppression (IS) is crucial for LTx patients to prevent organ rejection, but its effects on the immune system, especially T cell-mediated immunity, in patients with BC are not well understood. This study aimed to explore the immunological characteristics, particularly T cell subsets and their functions, in LTx patients with BC.

T Cell Subsets and Their Importance

Human T cells are diverse, with different subsets defined by the expression of CD45RA and CD62L. These subsets include naïve T cells (Tn, CD45RA+ CD62L+), stem cell memory T cells (Tscm, CD45RA+ CD62L+ CD95+), central-memory cells (Tcm, CD45RA- CD62L+), effector-memory cells (Tem, CD45RA- CD62L-), and terminally differentiated effector subsets (CD45RA+ CD62L-). Memory T cells are more efficient at controlling pathogens than naïve T cells. Tscm, a specialized subset of memory T cells, can differentiate directly from naïve precursors, reconstitute the full diversity of memory T cells upon antigen priming, and maintain their pool size through self-renewal. However, the differentiation of Tscm to other memory T cell subsets (like Tcm or Tem) and their role in LTx patients remain unclear.

Study Design and Participants

Participants

  • Patients with BC: 42 patients who underwent orthotopic LTx within one year at the First Affiliated Hospital of Xi’an Jiaotong University. BC was mainly biliary stricture confirmed by magnetic resonance cholangiopancreatography (MRCP) within 1 year after LTx. Blood samples were collected the next day after BC confirmation.
  • Transplant group without BC: Age-matched patients with stable liver function and no BC within 1 year after LTx. One patient with rejection was excluded.
  • Healthy controls (HCs): 18 age-matched healthy volunteers.

Ethical Approval

The study was approved by the Institutional Review Board (No. 2019 G-213), and all participants signed a written informed consent form.

Results

Blood Test Results

  • Liver Enzymes and Bilirubin: In the BC group, the levels of aspartate aminotransferase and total bilirubin were significantly higher compared to patients without BC.
  • Blood Cell Counts: Patients with post-LTx BC had a decreased absolute number of white blood cells and neutrophils, with a slightly increased proportion of lymphocytes (but similar absolute count). Three patients with infections in the BC group (18.75%) had C-reactive protein levels >10 mg/L on the day of T cell analysis.

T Cell Subsets in LTx Patients

  • CD4+ and CD8+ T Cells: After LTx, patients with BC showed decreased numbers of CD4+ T cells and increased numbers of CD8+ T cells compared to those without BC.
  • CD8+ T Cell Subsets: Significantly decreased numbers of Tn and Tscm, and increased numbers of Tem were observed in CD8+ T cells (but not in CD4+ effector T cells (Teff) or regulatory T cells (Tregs)).
  • Correlation Between Tscm and Tem:
    • In HCs: A significant negative correlation between Tscm and Tem (rather than with Tcm) was found in both CD8+ and CD4+ T cells. This suggests direct differentiation of Tscm to Tem.
    • In LTx patients: A negative correlation between Tscm and Tem was observed in CD8+ T cells (but not in CD4+ T cells). In LTx patients without BC, the correlation coefficient between CD8+ Tscm and CD8+ Tem was similar to that in HCs (-0.6318), while in LTx patients with BC, it was smaller (-0.5451).

T Cell Function in LTx Patients with BC

  • Co-inhibitory Receptors: Higher expression of PD-1 was observed in LTx patients with BC on CD4+ Teff, indicating Teff exhaustion.
  • Cytokine Production: CD4+ Teff and CD8+ T cells from LTx patients with BC also showed decreased interferon-γ or interleukin-2 production.
  • Tregs: No significant differences in CD39 and CTLA-4 expression on Tregs were found.

Discussion

T Cell Differentiation

Our results support the direct differentiation of Tscm to Tem. The decreased correlation coefficient between CD8+ Tscm and CD8+ Tem in LTx patients with BC may indicate decelerated differentiation of Tscm to Tem. Impairment of this differentiation may be more severe in CD4+ T cells in LTx patients, as shown by the lack of negative correlation between CD4+ Tscm and CD4+ Tem. T cell impairment was further supported by higher PD-1 expression and weakened cytokine secretion capacity in CD4+ T cells.

Implications for IS Therapy

The findings suggest that IS treatment for patients with post-LTx BC should be tailored more carefully. Precise immune monitoring of T cell differentiation is necessary. The observation that 87.5% of patients with BC were under FK506 suppression and 88% of patients without BC were under cyclosporin A IS (as shown in Supplementary Table 1) may be an interesting area for future large-scale studies.

Conclusion

This study provides insights into the compromised immune status, especially T cell-mediated immunity, in LTx patients with BC. It emphasizes the need for more individualized and precisely monitored IS therapy in these patients.

References

  1. Song JY, Du GS, Xiao L, Chen W, Suo LL, Gao Y, et al. Individualized immunosuppressive protocol of liver transplant recipient should be made based on splenic function status. Chin Med J 2016;129:1340–1346. doi: 10.4103/0366-6999.182828
  2. Gattinoni L, Speiser DE, Lichterfeld M, Bonini C. T memory stem cells in health and disease. Nat Med 2017;23:18–27. doi: 10.1038/nm.4241
  3. Takeshita M, Suzuki K, Kassai Y, Takiguchi M, Nakayama Y, Otomo Y, et al. Polarization diversity of human CD4+ stem cell memory T cells. Clin Immunol 2015;159:107–117. doi: 10.1016/j.clim.2015.04.010
  4. Khan O, Giles JR, McDonald S, Manne S, Ngiow SF, Patel KP, et al. TOX transcriptionally and epigenetically programs CD8(+) T cell exhaustion. Nature 2019;571:211–218. doi: 10.1038/s41586-019-1325-x
  5. Graef P, Buchholz VR, Stemberger C, Flossdorf M, Henkel L, Schiemann M, et al. Serial transfer of single-cell-derived immunocompetence reveals stemness of CD8(+) central memory T cells. Immunity 2014;41:116–126. doi: 10.1016/j.immuni.2014.05.018
  6. Wherry EJ, Teichgraber V, Becker TC, Masopust D, Kaech SM, Antia R, et al. Lineage relationship and protective immunity of memory CD8 T cell subsets. Nat Immunol 2003;4:225–234. doi: 10.1038/ni889

doi: 10.1097/CM9.0000000000001088

Was this helpful?

0 / 0