Page 1951 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 113 Human Leukocyte Antigen and Human Neutrophil Antigen Systems 1731

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on graft survival. Obviously, the degree of compatibility in the effect). 175–185 Both the GVHD and the GVN effect occur in the
context of allosensitization may vary according to the degree of presence of a full HLA match; thus the HLA molecules are not
mismatch between donor and recipient. In addition, alloantibodies targets of allosensitization themselves, but present polymorphic
are one aspect of alloreaction that does not take into account cellular molecules expressed by the recipient’s cells recognized by the grafted
responses. These have been more difficult to document, although immune cells.
they are likely to play an important role in the context of acute
transplant rejection. Several hypotheses have been discussed about
the reason or reasons for the capriciousness of allosensitization, GRAFT-VERSUS-HOST DISEASE
including the presence of regulatory immune responses or cytokine-
mediated immunosuppression. Currently the mechanism modulating GVHD represents the alloimmune reaction of donor lymphocytes
the quality and quantity of alloimmunity remains elusive, and differ- against normal cells of the recipient. GVHD occurs predomi-
ent aspects of this algorithm are discussed ad hoc in this chapter, with nantly in association with HSCT compared with other types of
particular attention to molecularly defined algorithms for the predic- transplants because the hematopoietic transplant is enriched with
tion of histocompatibility. 130,149,161,162 immune cells. Myeloablative therapy is generally administered
Clearly, HLA matching is beneficial in patients undergoing before transplantation and, as a consequence, in most cases prevents
renal transplantation. An analysis of more than 150,000 recipients graft rejection. GVHD is a major complication of HSCT, and a
receiving transplants in different centers participating in the Collab- fine balance between GVHD and graft rejection is maintained by
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orative Transplant Study showed that a complete mismatch (6 HLA- modulating the level of posttransplantation immunosuppression.
A+B+DR) had a 17% lower survival expectation than no mismatch In addition, other major disturbances associated with HSCT, such
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(p < .0001). Matching was particularly beneficial in patients with as overwhelming infection, leukemia, or tumor relapse, and other
highly reactive preformed alloantibodies. The same study suggested regimen-related morbidities are strongly influenced by the treatment
that high-resolution matching based on molecular typing improved of GVHD. With the advent of nonmyeloablative HSCT for the
graft survival. Similar results were observed in cases of cardiac treatment of nonhematologic diseases such as solid tumors, GVHD
transplantation in which HLA matching yielded significantly better has reached a predominant role because of its close association with
results (p < .0001). This is particularly important because donor GVN effect.
hearts are currently not allocated according to HLA match in most T-cell depletion has been advocated for the prevention of GVHD
centers. In cases of liver transplantation, HLA matching was not by decreasing the probability of cellular and humoral allore-
beneficial. 164 sponses. 186,187 This strategy decreases the occurrence of GVHD but
Donor-specific hyporesponsiveness has been particularly well is associated with an increased risk for graft rejection and tumor or
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documented in the context of renal allotransplantation and may leukemia relapse. In fact, Weiden et al observed that survivors
limit the need for immunosuppression. A recent randomized study of severe acute GVHD had a significantly lower incidence of tumor
suggested that pretransplant donor transfusions improved the survival relapse compared with patients who did not experience GVHD. This
of cadaver kidney grafts in patients receiving modern immuno- association appeared mandatory, and it was believed that the benefi-
suppressive regimens, but the mechanism remains unclear. 165,166 cial GVN reaction was inseparable from GVHD.
Although most centers currently do not implement deliberate blood The risk for GVHD increases with genetic distancing between
transfusions, the usefulness of this approach needs to be investigated donor and recipient. Thus recipients of transplants from HLA-
further. identical twins have a lesser chance of developing GVHD than
Approximately 5% to 10% of platelet transfusions are given to recipients of transplants from HLA-unrelated donors and from
patients who have been previously exposed to HLA class I-expressing donors with only a partial HLA match. 189,190 Interestingly, although
heterologous cells and are reactive to HLA antigens. Such patients the genetic closeness between donor and recipient appears to decrease
are refractory to random-donor platelets and must be given HLA- the risk for GVHD, it also decreases the therapeutic benefit, with
matched or semi-matched platelet apheresis components. 41–44 increased chances of tumor relapse.
However, a provision of HLA-matched platelets does not always
improve platelet recovery and survival. Possibly, the ineffective platelet
transfusion is in part caused by unrecognized HLA mismatches GRAFT-VERSUS-NEOPLASIA EFFECT
between the donor and recipient resulting from the low-resolution
methods used for typing, thus higher resolution methods have been It was originally observed that a beneficial collateral effect of GVHD
advocated. It is currently controversial whether or not molecularly was the rejection of neoplastic cells by the donor immune system in
based HLA typing confers an advantage over serologic typing, and the context of hematologic malignancies (graft-versus-leukemia
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this principle was recently questioned in the context of hematopoietic effect). It was rapidly recognized that the graft-versus-leukemia
cell transplantation. 167,168 effect could play a powerful therapeutic role in the treatment of
refractory malignant disorders, including some solid tumors (graft-
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versus-tumor effect). Because the biology and clinical principles
HUMAN LEUKOCYTE ANTIGEN AS A FUNCTIONAL underlining the two effects are likely similar, for simplicity, in this
MEDIATOR OF GRAFT-VERSUS-HOST DISEASE chapter we coin a unifying term: graft-versus-neoplasia effect. Indeed,
there is a perception that the GVN reaction is the most potent form
AND/OR GRAFT-VERSUS-NEOPLASIA EFFECT of tumor immunotherapy currently in clinical use. Its mechanism of
action is still poorly understood. T cells definitely play a fundamental
Allogeneic or syngeneic HSCT is used predominately for the treat- role in the initiation and maintenance of the alloreaction toward
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ment of hematologic malignancies 169–171 and other hematologic neoplastic cells. A sevenfold increase in the chance of relapse was
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disorders such as aplastic anemia, thalassemia, or myelodysplastic noted in patients with chronic myelogenous leukemia who received
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syndrome. This strategy can induce long-term disease-free survival a T cell-depleted HSCT as compared with a subset of patients who
in chronic myelogenous leukemia patients. 169,171 The objective of had received a T cell-depleted HSCT but did not develop GVHD. 186,187
HSCT in cases of malignancy is to cure the patient by eradication This result suggested that GVHD is a biologic entity different from
of the neoplastic cells with myeloablative chemotherapy followed the GVN effect. In addition, on leukemia relapse, administration of
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by restoration of hematopoiesis through the transplantation of donor lymphocyte infusion could reinduce clinical remission.
+
normal hematopoietic stem cells derived from HLA-compatible Finally, leukemia-specific CD8 T cells have been identified in circu-
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normal donors. This strategy is characterized by the insurgence of lating lymphocytes at the time of leukemia regression. NK cells
an immune reaction toward the host’s normal cells (GVHD) that play an additional role in mediating this phenomenon, and clinical
is often associated and preferentially targets neoplastic cells (GVN data suggests that mismatch of NK receptor and ligands during