Page 1139 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPter 81 Concepts and Challenges in Organ Transplantation 1105

CLiNiCaL PearLS powered to show overall superiority of one agent over the other
Treatment Options for Rejection and were powered to address safety rather than efficacy parameters
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or used a limited daclizumab dosage regimen. More robust
• Acute cellular rejection studies that are designed to evaluate the efficacy of rATG relative
• High-dose steroids to IL-2R mAbs specifically, are needed to definitively establish
• Rejection refractory to steroid treatment the use of rATG with respect to these monoclonal agents.
• Antithymocyte globulin
• Alemtuzumab Anti-CD52 Monoclonal Antibody (Alemtuzumab)
• Acute humoral rejection Anti-CD52 mAb (alemtuzumab) is a humanized rat IgG2b
• Plasmapheresis
• Intravenous immunoglobulin directed against the CD52 antigen, which is expressed on 95%
• Rituximab of peripheral blood lymphocytes, NK cells, macrophages, and
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thymocytes ; thus almost all mononuclear cells are affected.
The profound and long-lasting lymphopenia produced after the
administration of one or two doses of alemtuzumab is likely
Antithymocyte Globulin explained by such abundance on monocyte cell surfaces. Examina-
Rabbit-derived antithymocyte globulin (rATG) is a lymphocyte- tion of the peripheral blood lymphocytes from recipients after
depleting polyclonal IgG preparation with specificity toward alemtuzumab induction has identified a subset of T cells, pre-
human thymocytes. It binds primarily to the peripheral blood dominantly CD4 central memory cells that survive despite
lymphocytes as well as to those present in the lymphoid organs, alemtuzumab induction and appear largely resistant to depletion;
including lymph nodes, spleen, and thymus, as demonstrated these memory T cells express lower CD52 levels compared with
by in vivo studies in monkeys. The agent’s polyclonal nature naïve T cells. 28,29 CD52 is not present on granulocytes, platelets,
enables it to display specificity toward a wide variety of molecules erythrocytes, or hematopoietic stem cells (HSCs).
expressed on the surface of T cells, B cells, DCs, NK cells, and After binding to CD52, alemtuzumab causes cell death through
endothelial cells, including those involved in T-cell activation, several mechanisms: complement-mediated cytolysis, antibody-
proliferation, apoptosis, signal transduction, cell adhesion, and mediated cytotoxicity, and apoptosis. The plasma elimination
trafficking. half-life is approximately 12 days, whereas its clinical effects are
The precise mechanism of action underlying the immunosup- far more persistent. Lymphocyte depletion of >99% can be seen
pressive efficacy of rATG in SOT recipients is unknown at present, after a single dose, with lymph node depletion taking up to 3–5
although has been primarily attributed to T-cell depletion. Data days compared with <1 hour seen in the peripheral lymphocytes.
from in vitro studies have suggested that rATG modulates the Different subpopulations display varying rates of recovery,
expression of various lymphocyte surface antigens resulting depending on the subpopulation of interest: NK cells are almost
−
in apoptosis, antibody-dependent cytolysis, or complement- unaffected and decrease only transiently (a population of CD52
dependent lysis. Lymphocyte depletion with rATG has been NK cells has also been identified); monocyte and B-cell recovery
further demonstrated in adult recipients of renal transplants in can be seen at 3 and 12 months, respectively; T cells levels recover
several randomized, comparative clinical studies, with repopula- to only 50% of baseline at 36 months. 30
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tion reported to take at least 3 months. More recently, data Alemtuzumab is currently being used for induction in SOT
from preclinical and clinical studies have suggested that rATG with the aim of minimizing maintenance immunosuppression.
therapy may induce the expansion and enrichment of certain It was first used in transplantation as an induction agent in
+
+
+
+
31
Treg subsets, such as CD4 CD25 Forkhead box P3 (FOXP3 ), 1998, in 13 renal transplant recipients who received low-dose
+
+
CTLA-4 , and glucocorticoid-induced TNF receptor (GITR+) cyclosporine alone as maintenance therapy. At 6–12 months
Tregs from human peripheral blood lymphocytes or peripheral follow-up, patient and graft survival were 100%, and there were
24
blood mononuclear cells in vitro ; these Treg subsets are key to two episodes of acute rejection. The 5-year results of the initial
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immune response modulation and are further discussed in the series, together with another 20 patients who were subsequently
“Tolerance” section. enrolled, showed no significant difference in graft or patient
In terms of clinical use, rATG induction in combination with survival or in acute rejection rates compared with a retrospective,
tacrolimus-based immunosuppressive therapy is more effective contemporaneous control group of 66 renal transplant recipients
in preventing episodes of acute renal graft rejection than with who had received no induction, but triple immunosuppression
tacrolimus-based therapy without induction, as reported by therapy alone (cyclosporine, azathioprine, and prednisolone). The
primary endpoint data from two, randomized, open-label, study did also find, however, more episodes of late rejection in
multicenter trials. 25,26 Moreover, the median time to biopsy-proven the alemtuzumab-treated group. Indeed, severe lymphopenia and
acute rejection (BPAR) was >1 week longer in rATG induction homeostatic cytokines are known to drive the rapid homeostatic
than in noninduction; however, it should be noted that there proliferation of naïve and memory T cells, and lymphocytes
was no significant difference between induction and noninduction generated under such conditions have been previously found
regimens in terms of patient or graft survival. to be potent alloreactive cells, inevitably triggering rejection in
33
Several randomized, multicenter studies have reported that animal models. Investigation of this phenomenon in human
28
the efficacy of rATG induction therapy is generally no different recipients illustrated that the recovery of the immune system
from that of basiliximab or low-dose daclizumab (IL-2 receptor after alemtuzumab induction differed with respect to CD4 and
[IL-2R] mAbs, which are an alternative induction agent; discussed CD8 T cells. CD8 T cells recovered to pretransplantation levels
later in this section) with regard to the incidence of BPAR, graft by 6 months after alemtuzumab induction, whereas the number
loss, or death at 6 and 12 months after transplantation, in the of CD4 T cells remained low, even at 1-year after transplantation.
context of renal transplant recipients receiving triple immunosup- Repopulating CD8 T cells were mainly of the immunosenescent
−
+
pressive maintenance therapy. These trials, however, were not CD28 CD8 phenotype, and the percentage of this population