Immunophenotypic Analysis of Cellular Infiltrate of Renal Allograft Biopsies in Patients with Acute Rejection after Induction with Alemtuzumab (Campath-1H)

Abstract

Alemtuzumab is a humanized anti-CD52 mAb that has emerged as a safe and effective lymphocyte-depleting agent for induction therapy in renal transplantation. Recent reports have suggested that acute cellular rejection (ACR) of renal allografts in patients who receive alemtuzumab induction may be mediated by an atypical population of monocytes and not through "classical" T cell-dependent pathways of allorecognition. However, more recently, T cells with memory phenotype have been described in renal biopsies that were taken from alemtuzumab-treated patients who were experiencing ACR. This study investigated the cellular basis of ACR after alemtuzumab induction as compared with ACR that was associated with nondepleting therapy. Twelve biopsies from patients who were treated with a single dose of alemtuzumab at the time of transplantation and subsequently developed ACR were stained for the following cell markers: CD3 (T cells), CD68 (monocytes), CD20 (B cells), and CD45RO and CD45RA (memory and naïve T cells). ACR biopsies from six patients who received no induction therapy were used as controls. In alemtuzumab-treated patients, ACR occurred despite profound lymphopenia.

Potential of Noninvasive Serial Assessment of Acute Renal Allograft Rejection by 18F-FDG PET to Monitor Treatment Efficiency

“…In renal allografts, episodes of rejection are characterized by recruitment of activated leukocytes into the transplant (17,18,29). This is an integral part of the basic concept of the Banff classification, a commonly used score of renal rejection (7).…”

“…Analysis of the graft leukocyte pattern revealed massive upregulation of nearly all genes of pro-and antiinflammatory cell types analyzed on aTX postoperative day 4 ( (17,18,28,29). Upregulation of these genes (exception: neutrophil granulocytes: CD66, 3.1 6 0.3, P , 0.05) was not detected on aTX postoperative day 1 (meaning that significant graft infiltration had not yet started at that time).…”

“…Recently, using a uninephrectomized rat renal transplant model, we established 18 F-FDG PET as an entirely image-based method to assess acute renal rejection (16). Recruited activated leukocytes within the graft undergoing rejection (17,18) lead to a local increase in metabolic activity visualized and measured by accumulation of 18 F-FDG (16). However, no studies have yet established 18 F-FDG PET for the early detection and follow-up of therapy response (immunosuppressive treatment efficacy) in renal allograft rejection.…”

Memory Alloreactive B Cells and Alloantibodies Prevent Anti-CD154-Mediated Allograft Acceptance

“…Despite success of achieving long-term graft survival in murine models using anti-CD154 and tolerance induction in rodent models, it has proven difficult to establish allograft tolerance in larger animals, including nonhuman primates and humans (10,11). One hypothesis is that higher frequencies of memory alloreactive T lymphocytes are present in pretransplanted nonhuman primates and humans, and that these memory T cells have different activation requirements compared with naive cells (12).…”

Tolerance in Kidney Transplantation

“…They present different characteristics which prevent their manipulation in vivo. Indeed, it was shown that memory cells are resistant to depletion (Gallon et al, 2006), costimulatory blockade (Yang et al, 2007) and apoptosis (Wu et al, 2004) and can be activated by low antigenic signal and without costimulation (Cho et al, 2000). A lot of studies thus try to specifically target human memory T cells by neutralizing the tumor necrosis factor which is an important factor for the generation of memory T cells (Croft, 2003;Yuan et al, 2003) or by blocking adhesion molecules, then inhibiting the infiltration of such T cells in the graft (Ellis and Krueger., 2001;Dedrick et al, 2002;Vicenti et al, 2007).…”