Page 275 - Clinical Immunology_ Principles and Practice ( PDFDrive )

256 PART TwO Host Defense Mechanisms and Inflammation

MHC class I on NK-cell lytic function against tumors. However, resistant to NK-cell cytotoxicity. These findings are supported
how self-tolerance is achieved has been less clear. The initial by studies that show that high-risk, but uninfected, individuals
theory to explain self-tolerance was the “at least one receptor” appear to have increased NK-cell activity and that the combination
model, which proposed that NK cells must express at least one of the expression of HLA-Bw4 and the KIR3DS1 gene is associated
self–MHC class I inhibitory receptor. A second model suggested with delayed progression to AIDS. Finally, HIV viremia induces
that the receptor repertoire is shaped by selection by the specific several functional abnormalities on NK cells, suggesting that
MHC haplotype and the presence of self-ligands. The observation this complex virus and NK cells interact at multiple levels. 23
that NK cells are not autoreactive in the absence of any inhibitory
ligands (MHC class I–deficient mice) and are actually poor killers Control of Malignant Cells
suggests that the situation is more complex than these models NK cells were named as such during the early 1970s for their
allow for. A concept termed licensing was proposed to account potent ability to kill leukemia cell lines in vitro and since then
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for these observations. Under this model, NK cells are initially have been the focus therapies to boost cancer lysis in humans.
unresponsive or “unlicensed” and acquire functional competency Evading the immune system is a hallmark of cancer, but the
through binding of at least one inhibitory receptor before they can contribution of NK cells in tumor immune surveillance has been
be activated and display cytotoxic function. An alternative “disarm- difficult to assay as specific NK cell–deficient mouse models
ing” model proposes that all NK cells are initially responsive have only recently been generated. There is abundant evidence
but that chronic stimulation by normal cells renders these cells that NK cells can reduce tumor burden in animal models, and
unresponsive, or “anergic,” unless the stimulation is opposed by that the administration of cytokines that enhance NK-cell function
MHC class I–specific inhibitory receptors. More recently a third or number, including IL-2, -12, -15, and -21, or those that induce
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“rheostat” model has also been proposed, whereby the number IFN-α production, are protective against metastasis. In light
and affinity of inhibitory receptors it expresses tune NK-cell of this, many clinical trials have been conducted to assess either
18
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reactivity in a quantitative manner. Regardless of the exact cytokine treatment or the injection of ex vivo treated NK cells.
tolerance mechanism, it is interesting that unlike with T cells, Unfortunately, the high doses of IL-2 and IL-15 required for
there is no evidence for clonal deletion of autoreactive NK cells. efficacy are relatively toxic, and transferred NK cells have proved
difficult to target to tumors. Despite this, some successes have
SPECIFIC NK-CELL FUNCTIONS been demonstrated for melanoma, leukemia, and lung and hepatic
cancers. Today, numerous immunotherapy trials are ongoing
The ability to separate NK cells from T cells both phenotypically and aim to exploit and boost NK cell–mediated tumor killing,
and genetically has greatly enhanced the understanding of NK-cell including antibodies against inhibitory receptors on NK cells,
functions. Although some cytotoxic and immunomodulatory modified IL-2/IL-15 reagents, bispecific or trispecific and killer
capacities overlap with those of T cells, it is also apparent that engaging (BiKE or TRiKE) antibodies that bind NK cells and
some functions of NK cells are unique. Specific examples of tumor antigens, tumor-specific antibodies, in vitro expanded
NK-cell functions are discussed below. patient-derived NK cells, and irradiated NK cell lines, to name
a few. 18
Control of Viral Infections
NK-cell activity rises early in the course of viral infection, partly Role of NK Cells in Hematopoietic
driven by the release of IL-12, IL-18, and IFN-α/β, which stimu- Stem Cell Transplantation
lates activation (Chapter 25). The evidence that NK cells are
essential for host defense against viruses comes directly from CLINICAL PEARLS
patients and mice lacking NK-cell function and indirectly from Exploiting Natural Killer (NK) Cells in
viral strategies to avoid NK-cell recognition. Human patients Leukemia Therapy
with selective deficiencies in NK cells show a pronounced sus-
ceptibility to recurrent severe infections, especially with HSV Hematopoietic stem cell transplantation requires donor and recipient
and CMV. human leukocyte antigen (HLA) matching to reduce graft-versus-host
A powerful example of the role of NK cell–activating receptors disease (GvHD) mediated by transplanted cytotoxic T lymphocytes
(CTLs).
in viral control is NK cell–mediated resistance to MCMV. Mouse Haploidentical donors and recipients (those that share only one HLA
strains that lack Ly49H are highly susceptible to MCMV, leading haplotype) represent 50% of unrelated transplants and undergo a
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to uncontrolled viral replication and death. Importantly, this stronger conditioning regimen to avoid GvHD.
protection is mediated by the recognition of the m157 protein Alloreactive NK cells are present after haploidentical transplant and provide
+
of MCMV by Ly49H. The rapid accumulation of Ly49H NK a potent graft-versus-leukemia (GvL) effect in animal models.
cells during MCMV infection is the first example of clonal Transplantation from NK cell–alloreactive donors controls leukemia relapse
expansion of NK cells in a manner similar to that of B and T and improves engraftment without causing GvHD.
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cells. Surprisingly, these studies also found compelling evidence
for the maintenance of a long-lived NK-cell “memory”-like In humans, allogeneic bone marrow transplantation can cure
population (described below), blurring the line between innate leukemia through the reaction of donor CTLs in the graft
(NK cells) and adaptive (B and T cells) immune cells. against the residual leukemic cells. These transferred T cells also
As mentioned earlier, there is also evidence that NK cells have mediate GvHD. The need to prevent GvHD as a result of strong
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direct effects on the progression of HIV infection. NK cells are immunosuppression is the major cause of transplantation failure
able to lyse HIV-infected target cells either directly or by ADCC. because of infection and cancer relapse. It has been proposed
Despite this ability, NK-cell responses are impaired in patients that obtaining the transplant from a haploidentical donor (identi-
with HIV infection, as infected T-cell blasts selectively down- cal at one HLA haplotype and fully mismatched on the other,
regulate some HLA genes to avoid CTL activity but remain for example, a parent) provides allogeneic NK cells with an HLA