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Chapter 12. Other Forms Of Ifn Therapy
CHAPTER 12 OTHER FORMS OF IFN THERAPY I. IFN as an Antiviral Agent in Tumor Patients
The development of antiviral agents has expanded over the last years (see Galasso, 1981b). Several new antiviral drugs are being tested against clinical viral infections, and some of them are going to be used or are being used in combination with IFNs (cf. Luby, 1979; Chang and Snydman, 1979; Stringfellow, 1981). For general reviews on new trends in antiviral chemotherapy, see De Clercq (1979) and Liu (1982). Already in 1963, Old et al. reported their results on increased resistance to Mengo virus following infection with BCG. If this effect were due partly to induced I F N production, there is a rationale for using IFN therapy as an antiviral agent on some tumor patients. It has been postulated that there exists a definite host-mediated antiviral effect exerted by IFNs in in vivu situations (Bolhuis et al., 1981). There is also evidence, however, from experimental systems, that IFN might protect directly against viral infections rather than through activation of NK cells or exertion of other indirect actions (see Chong et al., 1983). Potent inhibitors of the replication of EBV in vitru have been found (Lin et al., 1983),and it would be interesting to combine these inhibitors with IFN treatment in experimental systems for further possible use in in uivo trials. Viral latency (see Tovey, 1980), in general, is probably of utmost importance for human disease. How the I F N system affects such viral persistance is unknown. IFNs have been used both in the treatment and the prophylaxis of human viral infections (see Merigan, 1982a,b). In the antiviral area it was discussed more extensively around 1981 whether IFN preferably should be used in combination therapy against virus infections (see Myers and Galasso, 1981-1982). It is of interest that it has been reported in the treatment of viral disease that synergistic effects can be achieved with the combination of antiviral drugs and human leukocyte IFN (Mecs et al., 1979). It is difficult to evaluate future possibilities for the use of IFNs in treating clinical infections by studying animal model systems. An important point is that the virus replication has gone on for quite some 185
186
12.
OTHER FORMS OF
IFN
THERAPY
time at the time the patients become symptomatic, and it can sometimes b y difficult to find corresponding models in animals (see Kern and Glasgow, 1981).Actually, the antiviral effects obtained by IFN in vivo might differ much from what has been seen in vitro (see Maheshwari et ul., 1983). This has implications, of course, also for the anti-tumor therapy, and it will also be important for determining the dose and schedule employed for IFN therapy. It should be mentioned that IFN-y has been claimed to be involved in the lymphokine components responsible for the restriction of chlamydia replication (Byrne and Krueger, 1983) and that IFN preparations have direct effects on the growth of chlamydiae (Rothermel et al., 1983). Falcoff et ul. (1966) were the first to treat viral infections with natural IFN-a, in this case cytomegalovirus (CMV) infections, with systemic low-dose IFN therapy. Another historical finding was the observation that concentrated human leukocyte IFN-a preparations containing 100 units of IFN injected intradermally had an effect on vaccinia lesions in monkeys (Scientific Committee on Interferon, 1970). Finally, monkey IFN was shown to reduce the infectivity of vaccinia in monkey eyes in 1960 (Cantell and Tomilla, 1960), and during the next year it was shown to be active against this virus also in monkey skin (Andrews, 1961). This type of IFN was then used in the first successful experiment with IFN in humans, where it afforded complete protection against vaccinia after local injections in 24 volunteers (Scientific Committee on IFN, 1962). It has been shown after that time in many diseases, employing many different preparations, that it can affect various virus infections (see Scott, 1983b). It has definitely been demonstrated that IFNs can have strong effects on ocular viral diseases (see Sundmacher et al., 1982), and IFN is probably of value for the treatment of ocular viral disease (Sundmacher et al., 1981; De Koning et al., 1981). For the effect of IFN on herpes simplex virus infections, cf. Ho et al. (1984). In this connection the experience in Israel on the treatment of life-threatening viral infections with IFN should also be mentioned (Levin et ul., 1982). When the antiviral drug acyclovir is employed on herpes virus infections, it must be remembered that virus production can resume when the drug is removed, and it has therefore already been suggested that such therapy should be combined with IFN (Hanto et al., 1982). Acyclovir seems to constitute an effective treatment for mucocutaneous herpes simplex virus infections in immunocompromised patients (Mitchell et al., 1981) and thus would be interesting to combine with IFN therapy in various situations. I n fact, IFN treatment has
IFN
AS AN ANTIVIRAL AGENT IN TUMOR PATIENTS
187
already been used in combination with acyclovir in dendritic keratitis in a double-blind study. The combination of acyclovir and semipurified human leukocyte IFN-a in such treatment seems to be excellent (Colin et al., 1983). The benefits of acyclovir in immunocompromised patients against herpes virus infections could perhaps be combined with various antiviral strategies employing the IFN system (Hann et al., 1983). Merigan et al. (1978b) demonstrated that semipurified human natural IFN-a has an effect on zoster progression, eliminates the distal cutaneous spread of this herpes virus, hastens pain resolution, and hinders visceral complications. In some patients with cancer it is obviously important to achieve antiviral effects and perhaps especially on zoster. In this context it is interesting to mention the convincing studies by the Stanford group with human leukocyte IFN-a as treatment for varicella in children. They made a randomized double-blind placebo controlled study in two phases. Forty-four children were treated within 72 hours after the exanthema appeared. All patients had malignant disease. It was seen that new lesion formation was delayed in the IFN-treated recipients, and by Day 7 few of the IFN-treated patients had developed new lesions. Also, it was found that among survivors treatment with IFN reduced the number of patients who had experienced life-threatening dissemination. The conclusion reached by using this type of therapy, which consisted of giving human natural leukocyte IFN-a at doses of 4.2 x lo4 IU/kg of body weight or higher per day (i.m. every 12 hours), was that the therapy had an antiviral effect in this immunocompromised patient group (Arvin et al., 1982). The Stanford University group has since concentrated on the treatment of hepatitis (see Scott, 1983b). The clinical experience up to 1983 in the treatment of viral infections and malignant diseases with natural IFN-P in West Germany was reviewed by Obert (1982).The anti-tumor results obtained by the principal investigators in these studies are presented in several sections, especially in Chapter 13 in this volume. It should be emphasized, however, that a study by Heidemann et al. (1982), in the treatment of herpes zoster, led to the first registration of any IFN, in this case natural IFN-6, as a drug for the treatment of a disease in any country. Also, in Cuba, I F N therapy has been tried on viral disease. Positive results in the treatment of hemorrhagic dengue fever with natural IFN-a were presented in 1982 (Limonta et al., 1982, 1983a). In an important series of double-blind placebo controlled trials Hirsch and collaborators showed that semipurified human leukocyte IFN-a is a useful agent for the prophylaxis of CMV infections in hu-
188
12.
OTHER FORMS OF
IFN
THERAPY
man renal transplant recipients (Cheeseman et al., 1979; Hirsch et al., 1981, 1982, 1983). In their latest study they treated patients with 3 x lo6 IU of IFN or placebo i.m. before transplant surgery was performed. After surgery the doses were reduced and given three times per week for 6 weeks and then twice a week for 8 weeks. It could be seen that the frequency of clinical CMV infections were reduced in the IFN recipients, that opportunistic superinfections only occurred in patients given placebo, and it was also concluded that minimal toxicity was observed with this type of IFN treatment. This is an interesting use of IFN since prophylactic treatment also in other studies seems to give rise to an effect on common virus infections (see Ingimarsson, 1980). Sixteen patients entered a study in Holland in which recombinant DNA leukocyte IFN-aA was given in a double-blind study started on renal transplant recipients (Kramer et al., 1984). There were eight patients in the IFN-treated group and eight in the placebo group. Acute rejection episodes were diagnosed in all patients between the second and seventeenth day after surgery in all eight IFN-treated patients, and in one of the eight placebo-treated patients. The rejection was of the acute vascular type. In addition, three IFN-treated patients had transient nephrotic syndromes. The IFN used had a specific activity of 2-4 x los IU/mg of protein, and it was given at a dose of 36 x 106 IU i.m. three times per week for 6 consecutive weeks followed by i.m. injections twice a week for another 6 weeks. The doses used in the studies were selected from rhesus monkey experiments in which similar doses per kg of body weight were prophylactic against intradermal vaccinia infections. The study indicates that large doses of IFN can probably have strong immunological effects, and, at least when this type of IFN is employed, one has to consider the side effects that can be obtained in patients at immunological risk. It has been suggested by Ahstram et al. (1974) that viral infections in leukemic children perhaps can be controlled by i.m. injections of human leukocyte IFN-a. Actually, this type of therapy has been used on many cases of childhood leukemia over the years at the Karolinska Hospital. The antiviral effects of various IFNs should now also be compared to other antiviral agents (see De Clercq et al., 1981). An effect of human leukocyte IFN-a purified by affinity chromatography using monoclonal antibody on human rhinovirus 9 in volunteers given by repeated nasal sprays was reported by Scott et al. (1982), but it is difficult at the moment to advocate IFN therapy for respiratory viral infections in humans (see Greenberg, 1984). Actually, it is hard to know at the moment where IFN stands among all the other antiviral
ADDITIONAL USES OF
IFN THERAPY
189
drugs that have been developed and are now being tested for infectious diseases in humans (see Galasso, 1981a).
II. Additional Uses of IFN Therapy
IFN preparations are now being used for the experimental treatment of various other types of diseases than viral and tumoral. One of the most interesting ones, concerning which a positive report has appeared, is multiple sclerosis (Jacobs et al., 1981).Jacobs et al. wrote a follow-up report (1982) on their multiple sclerosis patients and decided to start a large randomized study on multiple sclerosis patients. Six patients with multiple sclerosis were treated in Scandinavian studies (Osther et al., 1981) with systemic I F N therapy-natural IFN-a at a dose of 4 X lo6 IU of IFN daily for 5-16 months. The patients had a prehistory of 6-24 years of multiple sclerosis. There were no signs of any effect. The possible role played by IFN in multiple sclerosis will be exciting to follow, although it remains to be proved whether it is of importance at all in that disease (Vervliet et al., 1983a). It is of some interest for the tumor-IFN research area that multiple sclerosis patients given IFN-a seem to respond normally by preaugmentation (Rice et al., 1983). IFN is now being used also for the treatment of amyotrophic lateral sclerosis (A. Salazar, personal communication; W. Jablecki, personal communication; M. Farkkila, personal communication; R. Smith, personal communication). For a discussion of the effects of IFN on neurological diseases, see Abb et al. (1982b) and Johnson (1984). It is now clear that there are three clinically distinct disease syndromes in homosexually active men: (1)severe cellular immunodeficiency, (2) chronic benign lymphadenopathy, and, (3) Kaposi’s sarcoma (Schroff et al., 1983). In the acquired immunodeficiency syndrome patient materials the case fatality rate may exceed 90% after 2 years (see Gottlieb et al., 1983). These patients also develop a whole area of infectious complications, many of which are viral. In AIDS patients, the herpes viruses causing simplex, genitalis, and zoster are common (see Gilmore et al., 1983). Murray et. al. (1984) tested T lymphocytes from 16 patients with AIDS for their capacity to secrete macrophage-activating products including IFN-y. They found that mononuclear cells from 10 of 11 patients tested did not generate an effective lymphokine in response to mitogens, and 11 of 16 produced subnormal levels of IFN-y. Upon stimulation with antigens, cells from none of 40 tested patients generated any active lymphokines, and
190
12.
OTHER FORMS OF
IFN
THERAPY
cells from 13 of 14 completely failed to secrete any IFN-y. The antimicrobial function of monocytes from the patients was intact and once stimulated with normal lymphokines the patients’ monocytes responded with enhanced and effective intracellular antimicrobial activity. So the conclusion made by these authors was that impaired lymphokine production may predispose patients with AIDS to opportunistic infections. This would provide a rational for using IFN-y as immunotherapy for this particular disease. Another argument for the use of IFN therapy in AIDS patients is the association of Hodgkin’s and non-Hodgkin’s lymphomas with this disease (Dancis et al., 1984). It has by now been clearly established that IFN can exert effects on patients with lymphoma (see Chapter 10, Section 111).It is interesting that also interleukin 2 has been given to patients with cancer and with AIDS (Lotzeet al.,1984). Perhaps it could be combined with IFNs in future studies. A small investigation was made on five patients with Crohn’s disease by giving semipurified human IFN-P ism., four injections per week, each dose containing 2.4 x lo6 IU (Vantrappen et al., 1979). It was concluded that two cases showed objective improvement. In two other cases, there was marked clinical improvement but the endoscopic findings did not confirm this, and in the fifth patient there was no response to treatment. More and more diseases are being considered for IFN therapy, and IFN has even been tried for the treatment of severe psychiatric diseases (Cantell et al., 1980a).
The development of antiviral agents has expanded over the last years (see Galasso, 1981b). Several new antiviral drugs are being tested against clinical viral infections, and some of them are going to be used or are being used in combination with IFNs (cf. Luby, 1979; Chang and Snydman, 1979; Stringfellow, 1981). For general reviews on new trends in antiviral chemotherapy, see De Clercq (1979) and Liu (1982). Already in 1963, Old et al. reported their results on increased resistance to Mengo virus following infection with BCG. If this effect were due partly to induced I F N production, there is a rationale for using IFN therapy as an antiviral agent on some tumor patients. It has been postulated that there exists a definite host-mediated antiviral effect exerted by IFNs in in vivu situations (Bolhuis et al., 1981). There is also evidence, however, from experimental systems, that IFN might protect directly against viral infections rather than through activation of NK cells or exertion of other indirect actions (see Chong et al., 1983). Potent inhibitors of the replication of EBV in vitru have been found (Lin et al., 1983),and it would be interesting to combine these inhibitors with IFN treatment in experimental systems for further possible use in in uivo trials. Viral latency (see Tovey, 1980), in general, is probably of utmost importance for human disease. How the I F N system affects such viral persistance is unknown. IFNs have been used both in the treatment and the prophylaxis of human viral infections (see Merigan, 1982a,b). In the antiviral area it was discussed more extensively around 1981 whether IFN preferably should be used in combination therapy against virus infections (see Myers and Galasso, 1981-1982). It is of interest that it has been reported in the treatment of viral disease that synergistic effects can be achieved with the combination of antiviral drugs and human leukocyte IFN (Mecs et al., 1979). It is difficult to evaluate future possibilities for the use of IFNs in treating clinical infections by studying animal model systems. An important point is that the virus replication has gone on for quite some 185
186
12.
OTHER FORMS OF
IFN
THERAPY
time at the time the patients become symptomatic, and it can sometimes b y difficult to find corresponding models in animals (see Kern and Glasgow, 1981).Actually, the antiviral effects obtained by IFN in vivo might differ much from what has been seen in vitro (see Maheshwari et ul., 1983). This has implications, of course, also for the anti-tumor therapy, and it will also be important for determining the dose and schedule employed for IFN therapy. It should be mentioned that IFN-y has been claimed to be involved in the lymphokine components responsible for the restriction of chlamydia replication (Byrne and Krueger, 1983) and that IFN preparations have direct effects on the growth of chlamydiae (Rothermel et al., 1983). Falcoff et ul. (1966) were the first to treat viral infections with natural IFN-a, in this case cytomegalovirus (CMV) infections, with systemic low-dose IFN therapy. Another historical finding was the observation that concentrated human leukocyte IFN-a preparations containing 100 units of IFN injected intradermally had an effect on vaccinia lesions in monkeys (Scientific Committee on Interferon, 1970). Finally, monkey IFN was shown to reduce the infectivity of vaccinia in monkey eyes in 1960 (Cantell and Tomilla, 1960), and during the next year it was shown to be active against this virus also in monkey skin (Andrews, 1961). This type of IFN was then used in the first successful experiment with IFN in humans, where it afforded complete protection against vaccinia after local injections in 24 volunteers (Scientific Committee on IFN, 1962). It has been shown after that time in many diseases, employing many different preparations, that it can affect various virus infections (see Scott, 1983b). It has definitely been demonstrated that IFNs can have strong effects on ocular viral diseases (see Sundmacher et al., 1982), and IFN is probably of value for the treatment of ocular viral disease (Sundmacher et al., 1981; De Koning et al., 1981). For the effect of IFN on herpes simplex virus infections, cf. Ho et al. (1984). In this connection the experience in Israel on the treatment of life-threatening viral infections with IFN should also be mentioned (Levin et ul., 1982). When the antiviral drug acyclovir is employed on herpes virus infections, it must be remembered that virus production can resume when the drug is removed, and it has therefore already been suggested that such therapy should be combined with IFN (Hanto et al., 1982). Acyclovir seems to constitute an effective treatment for mucocutaneous herpes simplex virus infections in immunocompromised patients (Mitchell et al., 1981) and thus would be interesting to combine with IFN therapy in various situations. I n fact, IFN treatment has
IFN
AS AN ANTIVIRAL AGENT IN TUMOR PATIENTS
187
already been used in combination with acyclovir in dendritic keratitis in a double-blind study. The combination of acyclovir and semipurified human leukocyte IFN-a in such treatment seems to be excellent (Colin et al., 1983). The benefits of acyclovir in immunocompromised patients against herpes virus infections could perhaps be combined with various antiviral strategies employing the IFN system (Hann et al., 1983). Merigan et al. (1978b) demonstrated that semipurified human natural IFN-a has an effect on zoster progression, eliminates the distal cutaneous spread of this herpes virus, hastens pain resolution, and hinders visceral complications. In some patients with cancer it is obviously important to achieve antiviral effects and perhaps especially on zoster. In this context it is interesting to mention the convincing studies by the Stanford group with human leukocyte IFN-a as treatment for varicella in children. They made a randomized double-blind placebo controlled study in two phases. Forty-four children were treated within 72 hours after the exanthema appeared. All patients had malignant disease. It was seen that new lesion formation was delayed in the IFN-treated recipients, and by Day 7 few of the IFN-treated patients had developed new lesions. Also, it was found that among survivors treatment with IFN reduced the number of patients who had experienced life-threatening dissemination. The conclusion reached by using this type of therapy, which consisted of giving human natural leukocyte IFN-a at doses of 4.2 x lo4 IU/kg of body weight or higher per day (i.m. every 12 hours), was that the therapy had an antiviral effect in this immunocompromised patient group (Arvin et al., 1982). The Stanford University group has since concentrated on the treatment of hepatitis (see Scott, 1983b). The clinical experience up to 1983 in the treatment of viral infections and malignant diseases with natural IFN-P in West Germany was reviewed by Obert (1982).The anti-tumor results obtained by the principal investigators in these studies are presented in several sections, especially in Chapter 13 in this volume. It should be emphasized, however, that a study by Heidemann et al. (1982), in the treatment of herpes zoster, led to the first registration of any IFN, in this case natural IFN-6, as a drug for the treatment of a disease in any country. Also, in Cuba, I F N therapy has been tried on viral disease. Positive results in the treatment of hemorrhagic dengue fever with natural IFN-a were presented in 1982 (Limonta et al., 1982, 1983a). In an important series of double-blind placebo controlled trials Hirsch and collaborators showed that semipurified human leukocyte IFN-a is a useful agent for the prophylaxis of CMV infections in hu-
188
12.
OTHER FORMS OF
IFN
THERAPY
man renal transplant recipients (Cheeseman et al., 1979; Hirsch et al., 1981, 1982, 1983). In their latest study they treated patients with 3 x lo6 IU of IFN or placebo i.m. before transplant surgery was performed. After surgery the doses were reduced and given three times per week for 6 weeks and then twice a week for 8 weeks. It could be seen that the frequency of clinical CMV infections were reduced in the IFN recipients, that opportunistic superinfections only occurred in patients given placebo, and it was also concluded that minimal toxicity was observed with this type of IFN treatment. This is an interesting use of IFN since prophylactic treatment also in other studies seems to give rise to an effect on common virus infections (see Ingimarsson, 1980). Sixteen patients entered a study in Holland in which recombinant DNA leukocyte IFN-aA was given in a double-blind study started on renal transplant recipients (Kramer et al., 1984). There were eight patients in the IFN-treated group and eight in the placebo group. Acute rejection episodes were diagnosed in all patients between the second and seventeenth day after surgery in all eight IFN-treated patients, and in one of the eight placebo-treated patients. The rejection was of the acute vascular type. In addition, three IFN-treated patients had transient nephrotic syndromes. The IFN used had a specific activity of 2-4 x los IU/mg of protein, and it was given at a dose of 36 x 106 IU i.m. three times per week for 6 consecutive weeks followed by i.m. injections twice a week for another 6 weeks. The doses used in the studies were selected from rhesus monkey experiments in which similar doses per kg of body weight were prophylactic against intradermal vaccinia infections. The study indicates that large doses of IFN can probably have strong immunological effects, and, at least when this type of IFN is employed, one has to consider the side effects that can be obtained in patients at immunological risk. It has been suggested by Ahstram et al. (1974) that viral infections in leukemic children perhaps can be controlled by i.m. injections of human leukocyte IFN-a. Actually, this type of therapy has been used on many cases of childhood leukemia over the years at the Karolinska Hospital. The antiviral effects of various IFNs should now also be compared to other antiviral agents (see De Clercq et al., 1981). An effect of human leukocyte IFN-a purified by affinity chromatography using monoclonal antibody on human rhinovirus 9 in volunteers given by repeated nasal sprays was reported by Scott et al. (1982), but it is difficult at the moment to advocate IFN therapy for respiratory viral infections in humans (see Greenberg, 1984). Actually, it is hard to know at the moment where IFN stands among all the other antiviral
ADDITIONAL USES OF
IFN THERAPY
189
drugs that have been developed and are now being tested for infectious diseases in humans (see Galasso, 1981a).
II. Additional Uses of IFN Therapy
IFN preparations are now being used for the experimental treatment of various other types of diseases than viral and tumoral. One of the most interesting ones, concerning which a positive report has appeared, is multiple sclerosis (Jacobs et al., 1981).Jacobs et al. wrote a follow-up report (1982) on their multiple sclerosis patients and decided to start a large randomized study on multiple sclerosis patients. Six patients with multiple sclerosis were treated in Scandinavian studies (Osther et al., 1981) with systemic I F N therapy-natural IFN-a at a dose of 4 X lo6 IU of IFN daily for 5-16 months. The patients had a prehistory of 6-24 years of multiple sclerosis. There were no signs of any effect. The possible role played by IFN in multiple sclerosis will be exciting to follow, although it remains to be proved whether it is of importance at all in that disease (Vervliet et al., 1983a). It is of some interest for the tumor-IFN research area that multiple sclerosis patients given IFN-a seem to respond normally by preaugmentation (Rice et al., 1983). IFN is now being used also for the treatment of amyotrophic lateral sclerosis (A. Salazar, personal communication; W. Jablecki, personal communication; M. Farkkila, personal communication; R. Smith, personal communication). For a discussion of the effects of IFN on neurological diseases, see Abb et al. (1982b) and Johnson (1984). It is now clear that there are three clinically distinct disease syndromes in homosexually active men: (1)severe cellular immunodeficiency, (2) chronic benign lymphadenopathy, and, (3) Kaposi’s sarcoma (Schroff et al., 1983). In the acquired immunodeficiency syndrome patient materials the case fatality rate may exceed 90% after 2 years (see Gottlieb et al., 1983). These patients also develop a whole area of infectious complications, many of which are viral. In AIDS patients, the herpes viruses causing simplex, genitalis, and zoster are common (see Gilmore et al., 1983). Murray et. al. (1984) tested T lymphocytes from 16 patients with AIDS for their capacity to secrete macrophage-activating products including IFN-y. They found that mononuclear cells from 10 of 11 patients tested did not generate an effective lymphokine in response to mitogens, and 11 of 16 produced subnormal levels of IFN-y. Upon stimulation with antigens, cells from none of 40 tested patients generated any active lymphokines, and
190
12.
OTHER FORMS OF
IFN
THERAPY
cells from 13 of 14 completely failed to secrete any IFN-y. The antimicrobial function of monocytes from the patients was intact and once stimulated with normal lymphokines the patients’ monocytes responded with enhanced and effective intracellular antimicrobial activity. So the conclusion made by these authors was that impaired lymphokine production may predispose patients with AIDS to opportunistic infections. This would provide a rational for using IFN-y as immunotherapy for this particular disease. Another argument for the use of IFN therapy in AIDS patients is the association of Hodgkin’s and non-Hodgkin’s lymphomas with this disease (Dancis et al., 1984). It has by now been clearly established that IFN can exert effects on patients with lymphoma (see Chapter 10, Section 111).It is interesting that also interleukin 2 has been given to patients with cancer and with AIDS (Lotzeet al.,1984). Perhaps it could be combined with IFNs in future studies. A small investigation was made on five patients with Crohn’s disease by giving semipurified human IFN-P ism., four injections per week, each dose containing 2.4 x lo6 IU (Vantrappen et al., 1979). It was concluded that two cases showed objective improvement. In two other cases, there was marked clinical improvement but the endoscopic findings did not confirm this, and in the fifth patient there was no response to treatment. More and more diseases are being considered for IFN therapy, and IFN has even been tried for the treatment of severe psychiatric diseases (Cantell et al., 1980a).