Page 1867 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 108 Graft-Versus-Host Disease and Graft-Versus-Leukemia Responses 1659

are principal cellular targets of GVHD in the GI tract, where intes- prodrug of mycophenolic acid (MPA), a selective inhibitor of inosine
tinal flora are critical for amplification of GVHD damage. ISCs are monophosphate dehydrogenase, an enzyme critical to the de novo
protected by antibacterial proteins such as REG3α secreted by synthesis of guanosine nucleotide. Since T lymphocytes are more
neighboring Paneth cells. Mucosal barrier disruption caused by stem dependent on such synthesis than myeloid or mucosal cells, MPA
cell dropout and subsequent lack of mucosal regeneration may preferentially inhibits proliferative responses of T cells. 301
preferentially allow Paneth cell proteins, including REG3α, to tra- One hypothesis that flows from the three-step model of GVHD
verse into the bloodstream. Thus the plasma levels of REG3α may posits that reduction of intestinal colonization with bacteria could
serve as a “liquid biopsy” and surrogate marker for the cumulative prevent GVHD. Animal studies in germ-free environments support
area of these breaches to GI mucosal barrier integrity, a parameter this notion; GVHD was not observed until mice were colonized with
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impossible to measure by individual tissue biopsies. gram-negative organisms. Later, gut decontamination and use of a
laminar air flow environment was associated with less GVHD and
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better survival in patients with severe aplastic anemia. Similarly,
Prevention of Acute Graft-Versus-Host Disease studies of intestinal decontamination in patients with malignancies
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have shown less GVHD in some, 304,305 but not all studies. Finally,
Elimination of T cells with monoclonal antibodies, immunotoxins, another recent approach to GVHD prevention has been the use of
lectins, CD34 columns, or physical techniques are effective at reduc- nonmyeloablative conditioning transplants. Administration of vori-
ing GVHD. A typical unmanipulated marrow transplant entails the nostat in combination with standard GVHD prophylaxis after
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infusion of approximately 10 T cells per kg of recipient weight. A related-donor reduced-intensity conditioning hemopoietic stem-cell
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T-cell dose less than or equal to 10 per kg has been associated with transplantation reduced cumulative incidence of grade II–IV acute
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complete control of GVHD. More recently, the combination of GVHD by day 100 to 22%, lower than the expected incidence of
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very high stem cell numbers and less than 3 × 10 CD3 cells per kg severe acute GVHD. A less intensive preparative regimen decreases
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allowed haploidentical transplantation without GVHD. Presum- the tissue toxicity and subsequent release of cytokines in animal
ably host immune cells that survive the initial conditioning are models. 79,82 Patients generally experience mild toxicity in the initial
responsible for graft rejection. When the stem cell source contains peritransplant period and develop little or no GVHD, although many
large numbers of T cells, the GVH reaction further reduces the develop GVHD later, especially after donor lymphocyte infusions. In
residual population capable of alloreactivity, thus decreasing graft fact, the rates of GVHD are often higher than with conventional
rejection. To some degree, the higher graft failure rates may be con- transplants, and GVHD is associated with a significant portion of
trolled by increasing the intensity of the immunosuppression of the the GVL effect. 307–309
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conditioning regimen, 285,286 or adding back T cells. Overall there A recent study has shown that addition of one dose of a human-
has been no improvement in survival that can be definitively attrib- ized anti–IL-6 monoclonal antibody (tocilizumab) in addition to
uted to T-cell depletion. standard cyclosporine methotrexate prophylaxis resulted in only 12%
Treatment of established GVHD with specific T-cell antibodies Grade II–IV acute GVHD in 48 patients. 310,311 An important role for
has produced mixed results. Although antithymocyte globulin has TNF-α in clinical acute GVHD has been suggested by studies
definite activity in established GVHD, the nonspecific clearance of demonstrating elevated levels of TNF-α in the serum of patients with
T cells may result in increased opportunistic infections and no acute GVHD and other endothelial complications such as venooc-
improvement in survival. More specific therapy with the humanized clusive disease. 312–315 Therapy of GVHD with humanized anti-TNF-α
anti–IL-2 receptor antibody, daclizumab 288,289 or the humanized anti- (infliximab) 316,317 or a dimeric fusion protein consisting of the extra-
CD3 antibody, visilizumab 290,291 are promising, since they offer the cellular ligand-binding portion of the human TNF-α receptor
potential of selectively removing the activated T cells. However, an (TNFR) linked to the Fc portion of human immunoglobulin G1
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increased risk for infection may still be observed. 292 (etanercept) have shown some promise. 319,320 The second major
The first generally prescribed GVHD preventive regimen was the proinflammatory cytokine that appears to play an important role in
administration of intermittent low-dose methotrexate as developed the effector phase of acute GVHD is IL-1. Secretion of IL-1 appears
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in a dog model by Thomas and Storb. The principle of this to occur predominantly during the effector phase of GVHD in the
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approach was to administer a cell cycle–specific chemotherapeutic spleen and skin, two major GVHD target organs. IL-1RA is a
agent immediately after the transplant, when the T cells have started naturally occurring pure competitive inhibitor of IL-1 that is pro-
to divide after exposure to allogeneic antigens. Subsequently, the duced by monocytes/macrophages and keratinocytes. Of note, the
addition of antithymocyte globulin, prednisone, or both resulted in IL-1RA gene is polymorphic, and the presence in the donor of the
incremental improvement in the GVHD rate but no improvement allele that is linked to higher secretion of IL-1RA was associated with
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in survival. 294,295 Ultimately, the course of methotrexate was abbrevi- less acute GVHD. Two-phase I/II trials showed promising data
ated and combined with a T-cell activation inhibitor, such as cyclo- that specific inhibition of IL-1 with either the soluble receptor or
sporine or tacrolimus. The introduction of cyclosporine in the late IL-1RA could result in remissions in 50% to 60% of patients with
1970s was a significant advance in GVHD prevention. A similar steroid-resistant GVHD. 322,323 However, a subsequent randomized
agent, tacrolimus, has been shown to provide similar control of trial of the addition of IL-1RA or placebo to cyclosporine and
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GVHD. As a single agent, cyclosporine was about as effective as methotrexate beginning at the time of conditioning and continuing
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methotrexate. However, in combination with methotrexate, there through day 14 after stem cell infusion did not show any protective
was a significant reduction in the incidence of GVHD and an effect of the drug, despite the attainment of very high plasma
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improvement in survival. Subsequent trials of tacrolimus and levels. 271,324 Therefore, at least as administered in this study, IL-1
methotrexate compared with cyclosporine and methotrexate showed inhibition was insufficient to prevent GVHD in humans. IL-11 was
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no advantage for either combination. The addition of prednisone also able to protect the GI tract in animal models and prevent
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to the conventional two-drug regimen resulted in similar rates of GVHD, but it did not prevent clinical GVHD. Thus not all
GVHD and no improvement in survival. 299 preclinical strategies successfully translate to new therapies.
Sirolimus (rapamycin) is a macrocyclic lactone immunosuppres-
sant that is similar in structure to tacrolimus and cyclosporine. All
three drugs bind to immunophilins; however, sirolimus complexed Therapy for Acute Graft-Versus-Host Disease
with FKBP12 inhibits T-cell proliferation by interfering with signal
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transduction and cell-cycle progression and can prevent GVHD. Glucocorticoid steroids are the initial therapy for acute GVHD. The
Because Sirolimus acts through a separate mechanism from the mechanisms by which steroids work are multifactorial; they act as
tacrolimus-FKBP complex (and cyclosporine-cyclophilin complex), lympholytic agents and inhibit the release of inflammatory cytokines
it may be synergistic with both tacrolimus and cyclosporine. More such as IL-1, IL-2, IL-6, gamma interferon, and TNF-α. Because of
recently, mycophenolate mofetil (MMF) has been studied. It is the its intravenous availability, methylprednisolone is the steroid most