A Prospective, Randomized Study to Compare the Effect of Combination Therapy With Campath-1H on Peripheral Blood Mononuclear Cells in Kidney Transplant Recipients

Cravedi, Paolo (2009). A Prospective, Randomized Study to Compare the Effect of Combination Therapy With Campath-1H on Peripheral Blood Mononuclear Cells in Kidney Transplant Recipients. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000f262

Abstract

Induction therapy with Campath-1H, a humanized anti-CD52 monoclonal antibody depleting T and B lymphocytes, has been used in organ transplantation with the final goal of resetting the immune system in order to promote a tolerance-permissive environment and, at the same time, to reduce the need for chronic maintenance immunosuppression. To explore whether thisO may result from the capability of Campath-1H, in association with different maintenance regimens, to promote regulatory T cells (Treg) expansion and to assess whether this may translate into better graft outcomes in the long-term, 21 renal transplant patients receiving Campath-1H induction were randomized to low-dose SRL (n=11) or low-dose CsA (n=10), both in addition to low-dose mycophenolate mofetil (MMF) as maintenance immunosuppressive therapy and monitored for over 30 month follow-up.

SRL-treated patients showed an important expansion of circulating CD4⁺CD25^highFOXP3+ Treg that, at one and two years after transplant, were significantly more abundant than in the CsA group. T cells isolated from peripheral blood long-term post-transplant were hyporesponsive to donor alloantigens in both treatment arms. In SRL-, but not CsA-treated patients, hyporesponsiveness was reversed by Treg depletion. T cells from CsA-treated patients were anergic to donor antigens. Despite higher Treg counts, SRL-treated patients had a faster GFR and RPF decline, more clinical proteinuria, significantly higher tubular C4d staining score and a trend to higher chronic allograft damage index score, compared to CsA-treated patients. There was no significant correlation between Treg counts and any considered outcome variable in the study group as a whole and within each treatment group.

These data suggest that, after Campath-1H induction, maintenance therapy with low-dose SRL and MMF promotes Treg expansion, but this is not paralleled by long-term improved graft outcomes. Conversely, maintenance immunosuppression with low-dose CsA and MMF is associated with better graft function and structure than low-dose SRL plus MMF, possibly through the induction of T cell anergy toward donor antigens.