Download Role of Alloimmunity and Autoimmunity in the Pathogenesis of

Role of Alloimmunity and
Autoimmunity in the Pathogenesis of
Chronic Rejection
Introduction to Chronic Transplant
Rejection
• Solid organ transplantation is the treatment of
choice for the patients with end-stage renal
disease.
• The demand for solid organ donation still
vastly exceeds the number of suitable donors.
• These facts emphasize the importance of
defining the immunopathogenesis of rejection
to enhance the longterm graft survival
following solid organ transplantation.
• Rejection of the transplanted organ still remains a major challenge.
• It occurs in three major pathways—hyperacute, acute and chronic.
• However, prevalence of hyperacute and acute rejection of the graft
has decreased, owing to a significant improvement in donorrecipient matching, postoperative care and therapeutic strategy.
• But, there had been much less improvement in decreasing the
chronic rejection of the graft.
• Owing to its complicated immunopathogenesis, chronic rejection
still remains the leading cause of long-term allograft failure in
transplant recipients.
Risk Factors for Chronic Rejection
• Some of the risk factors that play a role in chronic rejection
include:
– Recurrent/refractory acute rejections
– Cytomegalovirus (CMV) and other viral infections
– Human leukocyte antigen (HLA) mismatches
– Organ ischemia, etc.
• Several nonspecific risk factors such as donor and recipient age,
graft ischemic time, and bacterial/fungal/non-CMV viral
infection have also been associated with decreased long-term
survival of the graft.
• These specific and non-specific risk factors cause inflammation,
which facilitates the induction of autoimmune responses against
selfantigens leading to chronic rejection and tissue remodeling.
Chronic Rejection:
Host-Anti-Graft-Immune Response
• The main characteristic for chronic rejection is
the fibrosis of graft parenchyma that develops
over months to years.
• The pathogenesis of chronic rejection is initiated
by a host-anti-graft-immune response.
• Both immune (antigen dependent) and
nonimmune (antigen-independent) factors lead
to fibroproliferative changes that cause occlusion
of tubular structures in the allograft.
Chronic Rejection:
Host-Anti-Graft-Immune Response
Alloantibodies in Chronic Rejection
• T helper cells that recognize processed forms of
soluble HLA in the context of self-major
histocompatibility complex (HLA) mediate the
chronic rejection of the graft.
• These T cells are possibly involved in the
development of antibodies (Abs) to donor HLA. It
is known that the presence of circulating
cytotoxic anti-HLA Abs has been strongly
associated with chronic allograft rejection of
renal transplants.
Chronic Rejection:
Host-Anti-Graft-Immune Response
Alloantibodies in Chronic Rejection
• Based on the data, it has been confirmed that anti-HLA Abs
activates human airway epithelial cells (AEC) that leads to the
production of several growth factors including fibrinogenic growth
factors.
• These growth factors play an important role in the pathogenesis of
chronic rejection of the graft.
• Chronic allograft nephropathy (CAN) is the leading cause of renal
function deterioration that accounts for nearly 40% of the graft loss
at 10 years.
• The factors that are associated with CAN include increased levels of
• pretransplant anti-HLA Abs, de novo posttransplant donorspecific
Abs and CD4+ alloreactive T cells.
Chronic Rejection:
Host-Anti-Graft-Immune Response
Development of Autoantibodies in Chronic Rejection
• Based on the data, it has been proposed that
autoimmunity plays an important role in the
pathogenesis of allograft rejection.
• The prevalence of glomerulopathy is 20% by the 5th
year posttransplant. According to a trial including
refractory vascular allograft rejection, it was confirmed
that presence of Abs directed at two epitopes of the
second extracellular loop of the angiotensin II type 1
(AT1) receptor was responsible for rejection.
• Therefore, detection of anti- AT1 receptor helps to
identify those at risk for refractory allograft rejection.
Towards an Unifying Model
• It was suggested that following transplantation,
an inflammatory environment is created within
the allograft that promotes alloantigen
presentation through both direct and indirect
pathways (see Fig. 1).
• Furthermore, inflammation and cell death
mediated by alloimmunity, and tissue remodeling
following transplantation can also lead to the
exposure of cryptic, but immunogenic,
selfantigens or their determinants.
Towards an Unifying Model
• Epitope spreading and activation of autoreactive
“lowaffinity” T cells that escaped the thymic deletion may
play a vital role in promoting allograft rejection.
• Under normal conditions, regulatory T cells can inhibit both
autoreactive as well as alloreactive effector T cells.
• However, currently used immunosuppressants have effects
on both effector T cells and more profoundly regulatory T
cells and therefore can facilitate loss of peripheral tolerance
to self-antigens.
• This can lead to immune responses to self-antigens, which
either alone or in combination with alloimmune responses
can lead to the pathogenesis of chronic rejection.
Conclusion
• Tissue inflammation, cell death mediated by
alloimmune responses and subsequent tissue
remodeling can result in exposure of self-antigens
and their antigenic determinants, leading to posttransplant autoimmunity.
• Identifying immune responses to donormismatched HLA antigens prior to the
development of immune responses to selfantigens may provide new approach to monitor
and prevent the development of chronic
rejection.