Immunomodulatory Impact of Rituximab and Thymoglobulin in Liver Transplantation

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Immunomodulatory Impact of Rituximab and
Thymoglobulin in Liver Transplantation

• Avinash Agarwal
• Richard A. Sidner
• Jonathan A. Fridell
• Rodrigo M. Vianna
• Mark D. Pescovitz
• A. Joseph Tector

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Tolerance

• The Holy Grail of transplantation
• Eliminate chronic immunosuppression and its
  associated morbidity
• Hypertension
• Renal failure
• Diabetes Mellitus
• Recurrent Hepatitis C (HCV)

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Hypothesis

• Antigen presentation by B cells may be important
  in acute rejection
• By combining B- and T-cell ablation, lymphocyte
  recovery could occur in the absence of antigen
  presentation
• This may lead to a tolerogenic environment

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Study Design

• Between 12/03 to 10/04, two nonrandomized,
  prospective immunosuppressive protocols were
  performed (n118)
• Groups
• T B-cell ablation (TB)
• T-cell ablation (T only)

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TB Depletion Immunosuppression Regimen

• No immunosuppression for first 48 hours
• POD 2
• Solumedrol
• 3 doses 500 mg, 250 mg, and 125 mg as
  premedication
• No further steroids
• Thymoglobulin
• 150 mg on day 2, 4, 6

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Immunosuppression Regimen (contd)

• POD 3
• Rituximab (anti human CD20)
• 150 mg/m2 given on POD 3
• Tacrolimus
• Started on POD 3 or 4
• 810 ng/mL by POD 7
• Chronic Immunosuppression
• Tacrolimus only
• Switched due to renal insufficiency or
  neurotoxicity
• Prednisone added for rejection

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T-only Regimen

• Identical to TB regimen except no B-cell
  depletion via Rituximab

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Demographics
No significant difference in gender, ethnicity,
nor primary disease HCV was predominant etiology
of liver failure (40)
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Results

• Clinical
• Patient and Graft Survival
• Rejection
• HCV recurrence
• Flow Cytometry
• Monitor lymphocyte recovery
• T and B cells, T-regulatory, and T-suppressor

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Patient Survival
Overall at 9 mo 87 vs. 85 Log rank test p
ns
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Causes of Death
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Graft Survival
Overall at 9 mo 85 vs. 85 Log rank test p
ns
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Causes of Graft Failure
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Prevalence of Rejection
Overall at 9 mo 6 vs. 14 Log rank test p
0.03

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HCV Recurrence
Overall at 9 mo 24 vs. 27 Log rank test p
ns
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T-cell (CD3) Recovery






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B-cell (CD19) Recovery








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T-Regulatory (CD4 25) Recovery







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T-Suppressor (CD8 28-) Recovery







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Conclusions

• Combined T- and B-cell depletion led to
  preferential recovery of immune regulatory cells
• Steroid avoidance may have a beneficial effect on
  HCV recurrence
• Further studies are necessary to determine the
  clinical impact of these immunomodulatory changes

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HCV Survival
Percent survival
Overall at 6 mo 92 vs. 83 p ns
Months
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Lymphocyte Homeostasis

• Lymphocyte population under negative feedback
  control
• The greater the depletion, the faster the
  recovery
• Select populations of memory or terminally
  differentiated recover faster than naïve cells