A particular, ongoing interest in NK cells, in addition to their intrinsic immunobiologic characteristics and functions, has been related to their potential roles in resistance to cancer and other diseases. As summarized below, and in large part reviewed previously , there has been mounting evidence that NK cells may be quite important in defence against disease.
The initial focus of in vivo studies was to explore the role of NK cells in resistance against established cell lines of tumours in vivo, particularly those that show susceptibility to cytolysis by NK cells in vitro. A major approach has been to look for correlations between resistance to the growth of the tumour cell lines in vivo and the levels of NK activity in the recipients. In several different situations, a good correlation was observed. The various types of correlations between NK activity and antitumour resistance have only been observed with tumour lines with some susceptibility to lysis by NK cells. The growth of NK-resistant tumours has not been affected by the levels of NK activity in the recipients.
Beige mice have low NK activity, due to a recessive point mutation and have also provided a convenient model for examining the role of NK cells in resistance to growth of transplantable tumour lines. Several NK-susceptible syngeneic tumours have been shown to produce a higher incidence of tumours and particularly of metastases in beige than in normal heterozygous lit-termates.
Another approach to the role of NK cells in vivo in the growth of transplantable tumours has been the attempt to transfer increased resistance by NK cell-enriched populations. Mixture of such cells with an NK-sensitive tumour resulted in reduced tumour incidence after transplantation. Systemic adoptive transfer of cells with the characteristics of NK cells from normal or nude mice was also found, in an immunochemotherapy model system, to increase protection against a transplantable leukaemia.
In an alternative approach that used information about selective markers on mouse NK cells, nude mice treated with anti-asialo GM1 (an antibody against a glycolipid which has selective reactivity against NK cells) had almost no detectable NK activity and showed increased susceptibility to transplantation of syngeneic, allogeneic and human tumours. Similarly, treatment of mice with anti-NK 1.1, an alloantibody with some specificity for NK cells, resulted in increased growth of a transplanted syngeneic tumour cell line.
The transfer of increased antitumour resistance with cell populations enriched in NK cells, and the inhibition of antitumour resistance by antisera reactive with NK cells, are quite supportive to the contention that NK cells play a key role in the limitation of growth of transplanted NK-susceptible tumour cell lines.
To obtain more direct information about the role of NK cells in the direct and rapid elimination of tumour cells in vivo, [l25I]-deoxyuridine (125IUdR)-labelled tumour cells were inoculated intravenously and clearance from the lungs and other organs was measured [41,42]. In mice with high NK activity, there was a greater clearance of radioactivity when measured at 2-4 hours after inoculation than seen in mice with low reactivity.
As further confirmation of the role of NK cells in resistance to growth of NK-susceptible transplantable tumours, transfer of NK cell-containing populations into mice with cyclophos-phamide-induced depression of NK activity was shown to restore significantly both tumour clearance and NK reactivity . The effectiveness of the transfer correlated with the levels of NK activity of donor cells in a variety of situations. As more conclusive evidence for the key role of NK cells, it was shown that highly purified populations of LGL could significantly restore clearance and NK activity in rats, which had been pretreated with anti-asialo GM1 , Thus, it appears that NK cells alone, without the need for other accessory cells, can effectively transfer the ability to rapidly eliminate radiolabeled tumour cells.
A similar pattern of results was obtained when radiolabeled cells were inoculated subcutane-ously into the footpads of mice . Clearance correlated in several ways with the levels of NK activity in the recipients and cells with the characteristics of NK cells were effective in local adoptive transfer.
The results with the footpad assay and the various demonstrations of NK-related differences in outgrowth of subcutaneous tumours indicate that natural effector cells can enter and be active at sites of local tumour growth. Thus, NK cells have the potential to be involved in the primary line of defence against the local outgrowth of transplanted tumours. However, it appears that the effectiveness of this natural resistance mechanism is rather limited. Even with tumour cells that are highly susceptible to NK activity, development of progressively growing tumours can occur in animals with high NK activity.
Effective control of tumour metastases is the central current issue in clinical oncology. There are increasing indications that NK cells may play a major role in host resistance against metastasis. The above-described ability of NK cells to rapidly eliminate intravenously-inoculated tumour cells might provide a very effective control of haematogenous spread of tumours. Experimental support for this possibility first came from the finding that cells from lung metastases of a transplantable tumour in mice were more resistant to NK activity than locally growing tumour cells . Metastatic tumour cells might represent those, which evaded elimination by relative resistance to NK activity. This posibility was supported by the demonstration that selection of NK-resistant variant tumour cells in vitro was accompanied by an increase in the metastatic capability of such cells in syngeneic hosts .
An important role of NK cells in resistance against metastatic growth of transplantable tumours was further supported by observations that suppression or augmentation of NK activity of mice was associated with parallel alterations in resistance to artificial metastases produced by intravenous inoculation of tumour cells . In addition, nude mice, which have elevated levels of NK activity, were found to have increased resistance to lung metastases, whereas beige mice, with deficient NK activity, developed increased numbers of lung metastases ,
The ability to selectively depress NK activity by administration of anti-asialo GM1 in vivo has provided a good opportunity to evaluate in detail the role of NK cells in control of metastases. Gorelik, et al.  showed that mice treated with this antiserum developed increased numbers of pulmonary metastases after intravenous inoculation of either B16 melanoma or Lewis lung carcinoma cells. In addition, the treated mice also developed many metastases in the liver, an organ, which previously showed completely resistance to the metastatic spread of these tumour lines.
By varying the time of inoculation of anti-asialo GM1 in relation to tumour challenge, it has been possible to gain some insight into the period of effective NK cell-mediated resistance to metastases . The most dramatic increases in metastases have been seen in mice treated with antiserum prior to tumour challenge. In contrast, administration of anti-asialo GM1 at one or three days following tumour challenge had little or no effect on the number of metastases that developed. Therefore, it appeared that NK cells primarily influence metastatic spread of tumours by acting during the phase of haematogenous dissemination, presumably by their ability to directly eliminate the tumour cells from the circulation or capillary beds. Once invasion of tumour cells into the parenchyma of the lungs or other organs has occurred, NK cells, at least without stimulation of their activity, would seem to have less or no influence on the growth of the tumour colonies.
A limitation to the conclusions to be drawn from experiments with anti-asialo GM1 was the possibility that the treatment also affected other effector mechanisms. Therefore, experiments were performed in rats treated with anti-asialo GM1, in which the depressed NK activity could be partially restored by adoptive transfer of highly purified LGL . This selective restoration of NK activity was accompanied by increased resistance to pulmonary metastases from a transplantable tumour cell line .
In contrast to the rather extensive evidence in experimental animal tumour models for an important role of NK cells in resisting the metastatic spread of tumour cells, there is a paucity of analogous information in cancer patients. However, the few relevant reports have been in concert with the animal tumour data. Pross and Lotzova  summarized results of studies of levels of NK activity in the blood of treated cancer patients who were free of detectable disease, who were then followed for possible development of distant metastases. A significant correlation between low NK activity and subsequent recurrence of disease was observed in several studies. Similarly, Schantz and Goephart  found that low NK activity at the time of surgical removal of squamous cell carcinoma of the head or neck was significantly correlated with subsequent development of distant metastases.
Taken together, the available evidence strongly suggests that NK cells play a major role in resistance against metastatic spread of tumours. The presence of NK cells in the blood, with spontaneous cytotoxic reactivity which can be rapidly augmented, may allow them to be particularly effective in eliminating most, if not all, tumour cells which seed into the circulation. Therefore, development of agents and protocols, which can induce sustained augmentation of NK activity may be expected to lead to more effective prevention and control of metastatic dissemination of tumours.
Of paramount interest is whether NK cells may be involved in immune surveillance against the initial development of spontaneous or carcinogen-induced tumours. There are several pieces of circumstantial evidence that are consistent with, or suggestive of, a role for NK cells:
a) Patients with the genetically determined Chediak-Higashi syndrome have a high risk of development of lymphoproliferative disease L54J. In detailed studies on several patients with this disease, all were found to have profound deficits in NK and K-cell activities, whereas a variety of other immune functions, including cytotoxicity against tumour cells by T cells, monocytes and granulocytes, was essentially normal.
b) Similarly, beige mice, which have an analogous genetic defect, also have a substantial , but incomplete , selective deficiency in NK activity. Aged beige mice have been reported to have a high incidence of lymphomas and heterozygous mice without the beige phenotype had a lower incidence .
c) Another human genetic abnormality, X-linked lymphoproliferative disease, has been associated with a defect in the ability to control proliferation of B cells infected with Epstein-Barr virus (EBV). Low NK activity has been found in such individuals and this deficit has been suggested to be involved in the pathogenesis of the disease , In support of this possibility, cells with the characteristics of NK cells have been found to inhibit the proliferation of autologous EBV-infected B cells in vitro .
d) Patients on immunosuppressive therapy after kidney allotransplants have a high risk of developing tumours, both haematologic malignancies and a variety of carcinomas. Patients on such treatment regimens have been found to have very low NK activity and this has been suggested as a contributing factor to the subsequent development of tumours , e) Patients with paroxysmal nocturnal haemaglobinuria also have a high risk of developing leukaemia and have been reported to have deficient NK activity [61 ]
f) A large prospective study has recently been reported , in which the residents in a Japanese city were tested for their levels of NK activity. During the following 15 years, individuals with initially low NK activity were found to have a significantly increased incidence of cancer.
4.4. Role in natural resistance against microbial infections
There have been increasing numbers of suggestions that NK cells may play some role in resistance against microbial infections. Most of the studies have been related to viruses , with several investigators showing that cells infected by a variety of viruses become considerably more sensitive to lysis by NK cells [64,65] and persistently virus-infected tumour cells grow poorly in nude mice, apparently as a result of interferon induction and reactivity by NK cells , Furthermore, resistance to infection by several types of viruses in vivo has been found to correlate with NK activity. There is considerable evidence for a role of NK cells in genetic resistance of mice to severe infection by herpes simplex virus type I , A correlation has also been found between susceptibility to severe herpesvirus infections in patients and low NK activity against virus-infected target cells , It also seems likely that NK cells play an important role in natural resistance to infection by mouse cytomegalovirus ,
NK cells may also be involved in resistance against some other types of microbial infections. A correlation has been observed between NK activity and resistance of mice to the malarial parasite Babesia microti , Beige mice were highly susceptible to infection whereas heterozygous normal mice were resistant. There has also been some suggestive evidence for a role of NK cells in infection by Trypanosoma cruzi and this parasite has been shown to be susceptible to cytotoxicity by NK cells in vitro , There is evidence that NK cells participate in eliminating tissue cells infected by mycoplasma or bacteria , NK cells also participate in regulatory interactions between immune cells and nonimmune cells. For example, NK cells are capable of directly upregulating polymorphonuclear leukocytes to kill Candida albicans , NK cells produce neutrophil-activating factors, which allow polymorphonuclear leukocytes to more effectively kill C. albicans and possibly other infectious organisms [71 J. NK cells may also play a role in natural resistance of mice to infection by the fungus Cryptococcus neoformans .
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