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Title: A prospective, randomized study to compare the effect of combination therapy with Campath-1H on peripheral blood mononuclear cells in kidney transplant recipients
Author: Cravedi, Paolo
ISNI:       0000 0004 2673 4774
Awarding Body: Open University
Current Institution: Open University
Date of Award: 2009
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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+CD25highFOXP3+ 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.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral