Page 1140 - Clinical Immunology_ Principles and Practice ( PDFDrive )

1106 Part NiNe Transplantation

was lower in those recipients who experienced rejection compared episodes as long ago as 1980. However, severe adverse effects of
with those who did not mount an immune response to their muromonab-CD3, such as cytokine-release syndrome (owing
allograft. A series of in vitro experiments demonstrated that the to the propensity of muromonab-CD3 to initially activate T
−
+
expanded CD28 CD8 T cells compete for immune space with cells, releasing TNF-α, and IL-2), resulted in preference for rATG
CD4 T cells, suppressing their proliferation and thus delaying and anti-CD52 agents, as outlined above. Furthermore, OKT3,
CD4 T-cell recovery. This delay might be associated with the an mAb of mouse origin, was limited by host production of
clinical outcome because CD4 T cells, notably CD4 T effector human antimouse antibodies (HAMAs) that bind to circulating
memory cells, have been shown to be associated with rejection. 34 reagent molecules, neutralizing their activity. Nonactivating,
Despite considerable experience with this agent over many therefore less toxic, humanized Fc-receptor nonbinding anti-CD3
years, largely in renal transplantation, until recently few random- mAbs, such as teplizumab and visilizumab, have been tested in
ized controlled trials had been conducted. Two randomized clinical trials in autoimmune disease settings (type 1 diabetes,
controlled clinical trials, the INTAC and 3C studies, investigating Crohn disease) as well as in renal and pancreatic islet transplanta-
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alemtuzumab induction in renal transplantation have now tion. Indeed, these studies have suggested a further mechanism
provided further insight. 35,36 The data from these studies support of action with regard to anti-CD3 antibodies, and this could be
the use of alemtuzumab as an induction agent in low-risk patients, helpful in the setting of transplantation: Circulating CD8 T cells
and the incidence of biopsy-confirmed acute rejection at 1 year isolated from patients with type I diabetes, after treatment with
was lower in patients treated with alemtuzumab compared with anti-CD3 mAb, may have regulatory function ex vivo; recent
those treated with basiliximab induction. Similar to ATG, data have demonstrated functional human CD8 Tregs in vivo
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alemtuzumab cannot be used as a solitary immunosuppressive after administration of anti-CD3 mAb. Further work is needed
therapy and requires long-term maintenance immunosuppression to elucidate the action of such agents on the immune response
to prevent allograft rejection. Importantly, in the 3C study, to both self and alloantigens to realize their full potential.
alemtuzumab induction therapy was found to result in reduced
CNI and mycophenolate exposure and steroid avoidance, reducing Anti-CD20 Monoclonal Antibody (Rituximab)
the risk of biopsy-proven acute rejection in a broad range of Rituximab is an anti-CD20, chimeric mAb that eliminates most
patients receiving a kidney transplant, and this supported earlier B cells from the circulation. Originally approved to treat B-cell
data from smaller studies, including a study in lung transplant lymphoproliferative diseases in patients other than transplant
37
recipients. However, patients with preformed DSAs despite a recipients as well as to treat posttransplantation lympho-
negative cross-match are at high risk of adverse outcomes when proliferative disease (PTLD), it is also now used in SOT as a
receiving a minimal immunosuppressive regimen incorporating treatment of antibody-mediated rejection and to desensitize
alemtuzumab induction; these patients may thus benefit from patients who are receiving ABO-incompatible transplants or
augmented immunosuppression. 38 retransplants. However, depletion of antibody-producing cells
+
Review of rejection episodes that have occurred with alem- may be incomplete because rituximab cannot target CD20 plasma
tuzumab induction, particularly in the absence of CNIs, has cells. It has been hypothesized that the action of rituximab in
highlighted some interesting findings. Several authors have allograft rejection is caused by not only depletion of plasma cells
reported that a number of these rejections demonstrate positive but also the effective depletion of APCs, which thus limits indirect
staining for the complement component C4d, indicative of acute pathway T-cell activation and a sustained immune response.
ABMR. In contrast, in acute rejection, examination of biopsy Clinical administration is in conjunction with maintenance
specimens taken from patients who had received both alemtu- immunosuppressive agents, plasmapheresis, intravenous immu-
zumab induction and tacrolimus revealed none that was humoral noglobulin (IVIG), and even splenectomy in some protocols. 43
27
in origin. These data suggest that tacrolimus may prevent this Recent work with nonhuman primate (NHP) models has
early ABMR. Immune profiles of renal transplant recipients shown that preemptive B-cell depletion with rituximab prevents
receiving alemtuzumab induction, 60 days of a CNI, and sub- both acute cellular rejection and antibody-mediated rejection
sequent sirolimus monotherapy displayed a general increase in of cardiac allografts; alloantibody was prevented from developing
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the naïve B-cell population. Bloom et al. subsequently showed in blood, and complement-mediated graft injury was avoided.
that B cell–activating factor (BAFF), a B-cell survival cytokine Not only was the B-cell response inhibited, but acute cellular
influencing the threshold of B-cell activation, substantially rejection was also reduced by the combination of cyclosporine
increased in renal transplantation following treatment with and rituximab, suggesting that B cells may play a role in acute
40
alemtuzumab. This observation may help explain and prevalent cellular rejection as well. There may be a role for targeting B
the development of alloantibody in patients treated with depleting cells preemptively in SOT, and additional strategies to down-
antibody therapy at the time of SOT. regulate the B-cell response are under evaluation. Promising
targets include BAFF and its receptor, as well as costimulatory
Signal 1: Blockade of Antigen Recognition molecules, such as CD28, CD154, and CD40. 44
Activation of the rejection response to an allograft hinges on
the recognition of antigen by the host immune system. Targeting Signal 2: Blockade of Costimulation
signal 1 through the use of mAbs has been used in both trans- In the absence of appropriate costimulation, partially activated
plantation and autoimmunity. T cells either become hyporesponsive to subsequent antigen-
specific TCR signals (donor-specific anergy) or die by apoptosis.
Anti-CD3 Monoclonal Antibody It has been hypothesized that the inhibition of full T-cell activation
Muromonab-CD3 (OKT3), a mouse mAb binding to the CD3 by costimulatory blockade rather than total T-cell depletion
component of the TCR signal–transduction complex, was used might more selectively target effector T cells and spare beneficial
successfully as an induction agent for high-risk patients or Tregs while avoiding the many adverse effects of nonspecific
for the treatment of corticosteroid-resistant acute rejection immunodepletion.