Subscribe to RSS
DOI: 10.1055/s-0035-1544473
Costimulation Blockade in a Heterotopic Thoracic Pig-to-baboon Cardiac Xenotransplantation Model
Objectives: New immunologic approaches are needed to overcome xenogeneic rejection to make clinical cardiac xenotransplantation possible. Anti-CD40-antibody reduces the adaptive immune response by inhibiting costimulation between T-cells and antigen presenting cells respectively B-cells. We investigated the effect on different peripheral cell lines during the first five days after transplantation.
Methods: Eight baboons underwent heterotopic thoracic cardiac xenotransplantation; double and triple (Gal-KO/hCD46/ ± hTM) transgenic pigs were used as donors. Treatment consisted of anti-CD20-antibody, MMF, tacrolimus, cyclophosphamide and ATG induction (dosage is listed in the table below). The last two animals additionally received the new anti-CD40-antibody (2C10R4). Lymphocytes, neutrophils, monocytes and thrombocytes were measured daily.
Results: The new therapeutic regimen used caused a clear decrease of neutrophils and lymphocytes compared with previous experiments. Additionally, the dose of cyclophosphamide, tacrolimus and MMF could be markedly reduced. This led to less side effects of the basic immunosuppression. No adverse effects of the new antibody, especially no thrombotic complications as described in other costimulation treatments occurred. Conclusions concerning graft survival are not possible at this point (one animal developed a pulmonary edema on day 13, one animal a sepsis on day 35; mean survival of previous animals was 18 days).
|
Control (n = 6) mean (± SD) |
Anti-CD 40 (n = 2) mean (± SD) |
Change (%) |
|
|---|---|---|---|
|
Immunosupressive regimen. |
|||
|
Tacrolimus (mg/kg) |
0.57 (± 0.11) |
0.37 (± 0.04) |
−36 |
|
MMF (mg/kg) |
373.66 (± 206.33) |
285.56 (± 12.58) |
−24 |
|
Anti-CD20 (mg/kg) |
34.88 (± 3.2) |
35.85 (± 3.05) |
+3 |
|
Cyclophosphamid (mg/kg) |
15.1 (± 9.36) |
4.72 (± 0.4) |
−69 |
|
Anti-CD40 (mg/kg) |
0 (± 0) |
153.95 (± 5.58) |
+100 |
|
Neutrophils (G/l) |
4.42 (± 2.68) |
1.75 (± 0.07) |
−60 |
|
Monocytes (G/l) |
0.45 (± 0.29) |
0.45 (± 0.21) |
+1 |
|
Lymphocytes (G/l) |
0.42 (± 0.39) |
0.2 (± 0.28) |
−52 |
|
Thrombocytes (G/l) |
399.83 (± 162.26) |
311 (± 111.72) |
−22 |
Conclusions: We could demonstrate that costimulation blockade with anti-CD40-antibody was efficient and the basic immunosuppression could be reduced. As a result the new therapeutic regimen had less toxic side effects compared with our control.