Transcript Mechanism and Treatment of Antibody

Mechanism and Treatment of
Antibody-Mediated Rejection
Reference: Stegall M.D, Gloor JM.
Deciphering antibody-mediated rejection:
new insights into mechanisms and
treatment. Curr Opin Organ Transplant.
2010;15:8–10.
• Antibody-mediated rejection (AMR) after
positive cross-match kidney transplantation is
a difficult situation for clinicians and so is for
the patient.
• However, now with better visibility in AMR
pathogenesis across varied clinical settings
and newer and better effective therapy
options are emerging.
Donor-Specific Alloantibody and
Rejectionsin Crossmatch Kidney
Transplantation
• Antibody-mediated rejection in positive
crossmatch kidney transplantation cases has
been attributed by a steep increase in the
donor-specific alloantibody (DSA) during the
initial few weeks of post-transplantation.
• The rise in DSA production could be due to the
plasma cells, which are already existing or
arising from recipient memory B cells.
• Through several sensitive crossmatch assays that are available
today, it has been established that renal transplant subjects have
DSA levels around a broad-spectrum and not all DSA lead to
hyperacute rejections.
• Donor antibody gives rise to diverse pathologic changes.
• Hence, AMR could be observed in association with cellular rejection
in an earlier unsensitized kidney recipient or AMR may occur only
due to antibody like the ones observed soon post-transplantation in
patients subjected to desensitization protocols for a positive crossmatch.
• Reasons for the development of AMR during the desensitization
phase are unknown.
• According to Burns et al. recipients with high levels of DSA in the
first month following transplantation almost invariably had AMR,
while patients with low DSA levels had no rejection.
Mechanisms of Antibody Production
during Antibody-Mediated Rejection
• Cellular mechanisms behind AMR are unknown; however,
recent studies indicate at the alloantibody produced in
sensitized patients as a major cause.
• Pre-existing plasma cells or the conversion of allospecific
memory B cells to plasma cells could be responsible for the
antibody production.
• Studies supporting the memory B cells activity during AMR
are not available.
• Irrespective of this various groups have created AMR
treatment protocols, built on their presumed effect on plasma
or B cells.
Current Treatment Modality for AMR
Intravenous Immunoglobulin and Plasmapheresis
• Currently, high-dose intravenous immunoglobulin (IVIGs) and
plasmapheresis (PP) are the chosen treatment protocols followed
for desensitization and AMR.
• Lefaucheur et al. studied the efficacy of both the treatment options
in recipients in the initial 3 months of post-transplant.
• The patients were treated for AMR with high-dose IVIg only or with
combination of IVIg/ anti-CD20/plasma-pheresis antibody,
rituximab.
• At 36 months, the graft survival in the patient group receiving IVIg
only and the IVIg/anti-CD20/plasmapheresis antibody, rituximab
was 50% and 91.7%, respectively.
• The study findings also reveal that in graft loss patients the level of
DSA post-treatment was higher.
• This and other studies do not give a clear picture on the effects of
rituximab on memory B cells or the efficacy of treating AMR with
only plasmapheresis.
Current Treatment Modality for AMR
Proteasome Inhibition for Treating AMR: A Novel Approach
• One way of treating AMR would be by controlling the DSA
production.
• Bortezomib, a proteasome inhibitor, approved by the FDA for
multiple myeloma can be used for AMR treatment.
• Bortezomib through apoptosis of normal plasma cells can reduce
production of alloantibody recipients under sensitization protocol.
• The role of proteasome inhibition for achieving low levels of DSA
has also been supported by Perry et al. In another study by Everly et
al.
• it was observed that patients who underwent proteasome
inhibition had lower levels of DSA but they also developed
transplant glomerulopathy.
• The absence of controls limits the opportunity of studying the true
efficacy of proteasome inhibition.
Current Treatment Modality for AMR
Use of Eculizumab Terminal Complement Inhibition
• C4d+ staining of the peritubular capillaries has
demonstrated the role of early complement activation
in AMR.
• Eculizumab, FDA-approved humanized monoclonal
antibody, which has high C5 affinity inhibits the
terminal complement activation.
• Locke et al. have studied the use of eculizumab in
successfully treating a severe AMR patient.
• Terminal complement can also prevent AMR
development.
Transplant Glomerulopathy
Development in AMR
• Transplant glomerulopathy, is a key chronic
damage seen in AMR, with above 40% of AMR
patients at the risk of developing the chronic
histologic lesion.
• Trivedi et al. studied the efficacy of bortezomib in
decreasing antibody levels through the denovo
production of anti-HLA antibodies.
• The authors advocate that the use of bortezomib
may prevent chronic antibody-mediated damage.
Conclusion
• Further investigation and follow-up are required to
evaluate if these novel therapies are effective enough in
enhancing AMR clinical outcomes.
• In addition, the immunologic mechanisms behind the
increased DSA levels and the role of memory B cells in
comparison to pre-existing plasma cells should be studied.
• Based on the occurrence of Banff criteria of AMR across
various seemingly dissimilar clinical settings, it is apt to
investigate if there are different ‘types’ of AMR existing.
• Also, it remains to be established whether chronic antibody
mediated injury will follow successful treatment of AMR.