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Targeting B Cells with Rituximab – A Novel Therapy for Renal Disease and Transplantation
unlike with some other biological agents. Extensive experience from its
Figure 1: Chimeric Rituximab Molecule
use in lymphoma patients has demonstrated the excellent risk/benefit
profile of the drug, and this appears to have been translated to its use in
immunological renal disease and transplantation. Indeed, more data exist
Murine
anti-CD20
from its use in rheumatoid arthritis, where the side effect profile appears
Chimeric
to parallel that reported in lymphoma studies, with a similar range of
rituximab
Human IgG1
adverse effects but occurring at a lower frequency. A more extensive backbone
analysis of adverse effects has recently been reviewed
3
and can be found
Human antichimeric
through the National electronic Library for Medicines (NeLM)
antibodies (HACAs)
(www.druginfozone.nhs.uk).
Cartoon representation of the chimeric rituximab molecule composed of murine variable
On rare occaisions, serious viral infections have been reported, heavy and light chains, directed against human CD20, on a human IgG1 backbone. The
including herpes, hepatitis and polyoma viruses. These have generally
murine protein may provoke an immune response, characterised by the development of
human antichimera antibodies (HACAs), illustrated in blue.
occurred in patients co-administered with chemotherapy. Recently,
the manufacturers have reported three cases of progressive multifocal
Figure 2: Immunohistochemistry for CD20 on Renal Biopsies from
leucoencephalopathy (PML) in patients treated with rituximab. These Patients with Class IV Lupus Nephritis, at (a) Low (x100) and
developed in two patients with SLE and one with cryoglobulinaemic
(b) High (x400) Magnification
vasculitis. All three had previously received significant doses of AB
immunosuppression, suggesting that the overall burden of therapy
may be responsible in certain susceptible patients rather than any
one individual agent. Details regarding this can be found at
www.druginfozone.nhs.uk or through the US Food and Drug
Administration (FDA) website (www.fda.gov/cder/drug/advisory/
rituximab.htm). Whether this represents a real increase in incidence
compared with that following other immunosuppressive protocols is
uncertain. Defining the critical susceptibility factors remains an important
task for the future. Since the variable portion of the molecule is of mouse
origin and therefore ‘foreign’ to the human immune system, it may result
The brown cells are the B cells. This demonstrates that there are focal areas of infiltration of
B cells within the interstitium. What role these cells play in disease pathogenesis remains
in the generation of human antichimeric antibodies (HACAs). These have
unclear, although they may be involved in lymphoid neogenesis and the promotion of local
been reported in some studies,
4–6
but their true incidence is unknown as
antigen presentation. They can also be found in other forms of glomerulonephritis, as well as
in cases of transplant rejection.
the majority of investigators do not seem to have routinely assayed for Courtesy of Professor Terry Cook, Department of Histopathology, Imperial College London,
them. Moreover, their clinical significance remains uncertain. The
Hammersmith Hospital.
potential complication arising from these antibodies may be a loss of
efficacy following repeated infusions, but this has yet to be seen. Indeed, glomerulonephritis (see Figure 2) as well as in rejecting renal grafts,
9
some have reported a prolongation of benefit following repeated dosing. suggesting that they may contribute to the immune-mediated
Analysis of HACA is planned in a prospective manner in some of the mechanisms.
9–12
Indeed, their persistence or disappearance from within
forthcoming trials. target organs such as the kidney following rituximab therapy may
correlate with clinical efficacy. More work is required to fully understand
the biological effects rituximab exerts in the context of autoimmunity and
transplantation. It has, however, provided us with important insights into
More work is required to fully
the mechanisms of autoantibody production, demonstrating that there
understand the biological effects
may be a population of short-lived plasma cells or a more immature B-cell
population producing them.
rituximab exerts in the context of
autoimmunity and transplantation.
Indications for Rituximab
As previously stated, no randomised trials comparing rituximab with
conventional therapy have yet been reported, although a number of
studies are ongoing. As such, its widespread use as a routine first-line
Rituximab in Renal Disease therapy cannot yet be recommended. Anecdotally, it has proved
Rituximab was introduced into the autoimmune field in the belief that invaluable as salvage therapy for certain patients in whom avoidance of
targeting B cells would be of benefit in antibody-mediated conditions, other immunosuppressives is required. Clinical trials that include
despite the fact that antibody-producing plasma cells are not depleted by rituximab as part of therapy in renal disease and transplantation are
rituximab. The diminution in autoantibody titres appears to be slightly required, and should be supported by governmental funding bodies or
variable despite clinical efficacy, suggesting that the compound may exert the manufacturers so that robust data regarding the efficacy of
its immunomodulatory effect through other mechanisms. Recent data rituximab can be generated.
from our laboratory and others have suggested that diminishing T-cell
activation
7
and augmenting T-regulatory cells may be as critical.
8
B cells Most data concerning the use of rituximab in renal disease have emerged
may be found in the kidney in a number of diverse forms of in the treatment of SLE and AAV. There are 28 reports of its use in SLE
EUROPEAN RENAL DISEASE 2007 63
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