Recipient memory-like lymphocytes remain unresponsive to graft antigens after CAMPATH-1H induction with reduced maintenance immunosuppression.
Trzonkowski P., Zilvetti M., Friend P., Wood KJ.
BACKGROUND: Treatment with CAMPATH-1H at the time of transplantation allows reduced maintenance immunosuppression. We hypothesized that CAMPATH-1H induction would modulate the response of repopulating leukocytes to donor alloantigens. METHODS: The phenotype, proliferative and stimulatory capacity of peripheral blood leukocytes from 14 renal transplant recipients treated with CAMPATH-1H and reduced immunosuppression with mycophenolate mofetil and tacrolimus were investigated for the first six months after transplantation. The impact of immunosuppressive drugs on leukocytes that escape depletion was also evaluated in vitro. RESULTS: CAMPATH-1H therapy caused a significant decrease in the number of B and T cells, with CD4 T central memory cells being the most resistant to depletion. The recovery of CD8 T cells was faster than that of CD4 T cells. Lymphopenia correlated with a decrease in both proliferative and effector responses, however, the recipient T cells remained responsive to third-party antigens. Dendritic cells (DC) were also depleted but to a lesser extent than lymphocytes; lymphoid DC were more resistant than myeloid DC; these changes correlated with decreased allostimulatory capacity. One of the patients experienced rejection that was treated successfully. The rejection was associated with a high proportion of CD4 T effector memory cells and myeloid DC, increased proliferation and enhanced effector activity to donor antigens. In vitro studies confirmed that the reduced dose of immunosuppressive drugs used could prevent activated T cells from switching to the effector compartment, suppressing both their proliferation and effector activity. CONCLUSIONS: CAMPATH-1H induction combined with reduced maintenance immunosuppression is sufficient to control the effector phase of immune response to donor antigens.