Donor-specific antibodies (DSA) and antibody-mediated rejection have gained significant
attention recently due to their serious consequences, but there are limited effective
treatments for persistent DSAs in patients without graft dysfunction due to their
associated severe side effects. Our center demonstrated that extracorporeal photopheresis
(ECP) can potentially reduce the mean fluorescence intensity of dnDSAs in recipients with
antibody-mediated rejection (AMR), suggesting it as a safe option for treating
subclinical AMR with dnDSAs and inducing tolerogenic immunomodulation in this complex
population.
The hypothesis underlying the proposed randomized controlled trial is that ECP might have
the potential to reduce the burden of de novo donor-specific antibodies after lung
transplantation, by modulating host humoral alloresponse and promoting tolerance, without
provoking side effects.
Our primary objective is to evaluate the therapeutic effect of ECP in terms of reduction
of dnDSAs titer in clinically stable patients with persistent (>6 months) dnDSAs
(MFI>1000). As secondary objective, we intend to assess the therapeutic effect of ECP on
incidence of clinical AMR, ACR, CLAD, survival and occurrence of infectious complications
as well as the rate of adverse effects. Our experimental objectives are to provide an
in-depth analysis of the immunological effects of ECP.
80 patients with persistent dnDSAs (> 3 months) with a MFI > 1000 will be randomized into
two groups. Each group will include 40 patients. Patients will be stratified according to
the presence of HLA-DQ. The control group will be observed and no active treatment will
be administered. This is our standard of care in the studied clinical situation.
Treatment group will receive extracorporeal photopheresis. First, a two-day treatment
cycle will be performed once every second week for the first two months. Then, a two-day
treatment cycle will be performed once a month for 6 months. To elucidate the specific
mechanisms of ECP in modulating humoral alloresponse, a series of studies are planned: 1)
flow cytometric immunophenotyping, 2) miRNA expression profiling, 3) cytokine expression,
4) gene expression signature of PBMCs, 5) proteomic characterization.
The proposed study aims to address this clinical need by investigating the effects of a
safe therapeutic modality such as ECP. This study may have a dual benefit: first, it may
reduce the burden of dnDSAs in lung transplant recipients, thereby reducing the incidence
of antibody-mediated rejection, and second, it may promote host tolerance to the graft.
In addition, we will investigate the immunomodulatory mechanisms of ECP in the context of
humoral allogeneic response, which has not been previously investigated.