Page 1143 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPter 81 Concepts and Challenges in Organ Transplantation 1109

tHeraPeUtiC PriNCiPLeS KeY CONCePtS
Mechanisms of Tolerance Barriers to Transplantation Tolerance

Deletion • T-cell memory
Deletion of alloreactive or autoreactive T cells can be achieved centrally • Presensitization—direct exposure to alloantigen (i.e., pregnancy or
in the thymus or in the periphery. Infusion of donor bone marrow into blood transfusion).
a recipient who has been conditioned with nonmyeloablative irradiation • Heterologous immunity—cross-reactivity in the T-cell repertoire
or immunotherapy enables antigen-presenting cells (APCs) to access among antiviral, antibacterial, environmental, and transplantation
the thymus and trigger the deletion of maturing thymocytes. In the antigens.
periphery, deletion can be triggered by alloantigen recognition under • Homeostatic proliferation—induced by immunodepletory antibodies
suboptimal conditions, including costimulation blockade, as well as (i.e., alemtuzumab).
immunodepletion by activation of apoptotic cell death and cytolysis. • Memory T cells generated by the above mechanisms—can result
in rapidly formed effector immune responses upon rechallenge.
anergy These T cells are less sensitive to T-cell depleting antibodies and
This is the functional inactivation of the T-cell response to restimulation costimulatory blockade and thus may be more resistant to some
tolerance induction strategies.
by alloantigen or self antigen and has been described both in vivo and • B-cell response
in vitro. Some forms of T-cell anergy are also reported to result in the
development of regulatory activity. Costimulation blockade, as well as • Recipients treated with immunodepletory antibodies display a general
increase in the naïve B-cell population.
inhibition of downstream proliferative pathways, can trigger anergic states
in T cells. • There is a prevalent development of alloantibody in recipients treated
with depleting antibody therapy.
• Much focus of tolerogenic strategies is on the T-cell response.
immunoregulation However, recent data suggest that the humoral immune system
This active process results in the regulation of one cell population may play a more significant role than previously thought, possibly
by the activity of another cell population. Various populations of contributing to more long-term outcomes. Further work in this area
leukocytes have been described as having the ability to control immune continues.
responsiveness to alloantigen stimulation in both innate and adaptive • Lack of tolerance signature
immune responses. This mechanism, although well described in experi- • An episode of acute rejection can severely affect graft survival in
mental models, has yet to be introduced therapeutically in a sustained, most transplanted organs.
clinical setting. • There is absence of validated biomarkers of tolerance or predictors
of rejection.
Clonal exhaustion • It is clinically difficult to justify often high-risk tolerizing strategies
This can occur as a result of chronic antigen stimulation or antigen recogni- in patients who would otherwise do moderately well with standard
tion under suboptimal conditions. The consequence is either deletion or immunosuppression.
functional inactivation of the cells responding to the recognized antigen.
An example of such exhaustion can be seen in liver transplantation,
where the large number of donor-derived APCs migrating from the liver
to draining lymphoid tissues after transplantation can trigger this type
of response.
In the next section, we discuss the current clinical strategies
ignorance for tolerance induction as well as much-needed future approaches
This is an uncommon mechanism in the induction phase of unresponsive- to produce more short-acting, antigen-specific agents that can
ness to alloantigen as it is difficult to introduce donor cells or tissue optimize outcomes in the clinic.
without alerting the immune system to their presence, in transplantation.
This mechanism, however, does describe the natural state of some Molecule-Based Tolerogenic Protocols
self-reactive CD4 T-cell populations found in healthy individuals with no The induction of COT through the administration of presumed
autoimmune pathology.
tolerogenic drugs and subsequent immunosuppression minimiza-
tion is one such strategy currently under investigation. Promising
results of the first use of alemtuzumab in human subjects by
Calne et al. 31,62 with low-dose cyclosporine alone as maintenance
therapy introduced the concept of “prope” tolerance (i.e., graft
lack of definitive laboratory parameters able to give a clear acceptance with reduced immunosuppression). Several groups
indication of whether a particular recipient is tolerant of his or have subsequently studied alemtuzumab induction and main-
her graft. Furthermore, COT appears to be somewhat organ tenance therapy without nephrotoxic CNI agents. Unfortunately,
dependent. Recipients of a liver graft are more capable of develop- results of pilot studies have been poor, with high acute rejection
ing COT because of the immune-privileged status of the liver rates (as much as 36% of recipients in one study). As discussed
(see Fig. 81.7). Clinical experience in liver transplantation now above, an attempt to induce donor allograft tolerance using
demonstrates clear evidence that a permanent and stable alemtuzumab alone as an induction therapy with no maintenance
immunosuppressive-free state can be safely attempted and immunosuppression at all resulted in all of the patients developing
31
sometimes achieved in patients who have received a liver trans- acute rejection within the first month after transplantation.
59
plant for nonimmunological liver diseases. However, COT has Encouragingly, physicians from the University of Wisconsin have
never been reported after intestinal, islet, or whole-organ pancreas demonstrated excellent long-term graft survival in 90% of patients
transplantation, whereas two exceptional cases of COT have been maintained with only low-dose rapamycin monotherapy; these
described after lung and heart transplantations. 60,61 Since the recipients had undergone alemtuzumab induction and an initial
first renal transplant over 55 years ago, only sporadic cases of 60-day-only treatment with a CNI after transplantation to prevent
COT have been documented after renal transplantation in the acute rejection. It should be noted, however, that 50% of the
absence of genetic identity between donor and recipient. 59 patients developed alloantibody to either HLA class I or II