To explain the underlying immunological mechanisms for rejection under belatacept treatment, the phenotypical and functional characteristics of graft infiltrating lymphocytes were studied during rejection under belatacept, and the characteristics of alloreactive lymphocytes in mixed-lymphocyte reactions were studied in the presence of belatcept.

A 61-year old female received her first, cross-match negative, 1-2-2-mismatched kidney-transplant from her husband. The initial post-operative course was uneventful. Fifty-six days after transplantation she was admitted because of fever, graft tenderness and acute kidney failure. Consequently she was treated with pulse glucocorticoids (1000 mg/day intravenously for three consecutive days). Renal biopsy demonstrated a severe Banff grade II vascular rejection with T – and B cell infiltrates, large vessel thrombosis and massive necrosis. Because of absent transplant-perfusion, a nephrectomy was performed and graft infiltrating lymphocytes were isolated.

CD86 on peripheral CD14+ monocytes was completely blocked by belatacept before and during rejection. 60-70% of the graft infiltrating T-lymphocytes were CCR7+CD45RO+ effector-memory CD4 and CD8 T-lymphocytes. 5% of the CD4+ and 51% of the CD8+ T-lymphocytes did not express CD28. Ex vivo, 50% of the CD8+CD28null T-lymphocytes expressed granzyme B, an important component of the lytic machinery of cytotoxic cells. In addition a high IFNγ-production capacity (64%) was measured by these CD8+CD28null T-lymphocytes. However, also 47% of the CD8+CD28pos T-lymphocytes expressed granzyme B and had a great IFNγ-production capacity (66%). CD4+ lymphocytes did not express granzyme B, but 39% produced IFNγ upon stimulation. This was in line with the in vitro allogeneic IFNγ-production by patients' CD28null and CD28pos T-lymphocytes, which was not inhibited by belatacept. The highest levels were measured in T-lymphocytes that had lost their CD28 molecules.

From this combination of in vivo and in vitro data can be concluded both IFNγ and granzyme B-producing CD28null and CD28pos T-lymphocytes contributed to rejection under belatacept treatment.

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