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The thymic hormones in the treatment of immune deficiency related to HIV infection
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Pharmacological Research, Vol. 26, Supplement 2, 1992
THE THYMIC HORMONES IN THE TREATMENT OF IMMUNE DEFICIENCY RELATED TO HIV INFECTION Gianotti N, Finazzi R, Uberti Foppa C, Danise A, Migone T and Lazzarin A . Istituto Scientifico San Raffaele Divisione di Malattie Infettive, Via Stamira d'Ancona, 20 - 20127 Milano Key words : Thymostimulin - Thymopentin - HIV infection The lack of antiretroviral drugs of proven effectiveness during the first years of the spread of AIDS, led to undertake therapeutic trials with drugs potentially capable of stimulating the function of the most compromised cellular network in HIV infection (CD4+ T-lymphocytes) . The aim was to block the progression of the immune deficiency and consequently, to reduce the incidence of opportunistic infections due to cell-mediated immunological defects . Compounds owning to the latter cathegory may include interferons, interleukin-2, isoprinosin, diethyldithiocarbamate, and thymic hormones such as thymostimulin (TP1) and thymopentin (TP5) . Thymostimulin is a natural multifactorial extract of bovine thymus, while thymopentin is a synthetic pentapeptide representing the linear sequence of those five thymopoietin aminoacids which probabily form its active site . The rationale for using thymic hormones in HIV infection, besides the obvious attempt to restore immunocompetence, was based on the evidence of a severe thymic displasia in AIDS patients (1) . Their mechanism of action is still unclear and likely to be complex, as they probably act on the maturation and the differentiation of T-lymphocytes at different levels : within the bone marrow in the phase of switching from stem cell to thymocyte (i .e . on prothymocytes), within the thymus, and within the peripheral lymphatic system . However, it has been argued that thymic hormones could enhance the stimulation of target cells carring an integrated virus, and this might favour the development of latent HIV infection . Moreover, the disappointing results of some pilot studies in patients with full-blown AIDS and AIDS-related complex (ARC), made long term trials with these drugs in the early stages of infection unreasonable . Subsequently, it seemed more rational to associate the standard antiretroviral treatment with immune response modifiers more strictly involved in the HIV-related pathogenetic mechanisms, particulary if at least potentially endowed with antiretroviral activity (interferons, interleukins) . Here we report the results of some our pilot studies with thymic hormones carried out between 1985 and 1986, when antiretroviral drugs of proven effectiveness against HIV were not yet available . The first was conducted in nine case of persistent generalized lymphadenopathy (PGL) treated with thymostimulin 1 mg/Kg/day im for 15 days, and 1 mg/Kg/week the following 45 days(2) . In the treated patients we observed an increase in the absolute number and in the percentage of CD4+ T-lymphocytes during the first two weeks of treatment ; the increase was rapid (within seven days) and accompanied by a parallel augmentation of the CD4+/CD8+ ratio . Nevertheless, these figures returned to basal values six months after the 1043-6618/92/26110062-02/$03 .00/0
© 1992 The Italian Pharmacological Society
Pharmacological Research, Vol . 26, Supplement 2, 1992
beginning of the trial . In the control group a further decrease of CD4+ T-lymphocytes was noticed during the same period . A policentric study of 34 patients treated with TP1 (1 mg/Kg/day for 15 days, and then 1 mg/Kg twice a week for six months) showed a more lasting (up to six months) increase in the absolute number of CD4+ T-lymphocytes, and a higher (though not statistically significant) absolute number of CD4+ T-lymphocytes at the end of the year of observation compared to basal values (3) . These changes in laboratory parameters paralleled a similar improvement of the clinical features, particulary regarding to costitutional symptoms . In a third study, eight patients with PGL were given thymopentin 50 mg three times a week s .c . for three weeks, and 50 mg/week s .c . for three months three months later (4) . In the treated group the absolute number of CD4+ T-lymphocytes and the response to mitogens were significantly increased (p 0,05 and p 0 .01 respectively) ; moreover, at the end of the first cycle, the chemotaxis of neutrophils returned to normal values . The results of these studies show a clearcut, though transient, effectiveness of thymic hormones on improvement of CD4+ T-lymphocytes funtions and absolute number . Nevertheless, a prospective study on clinical outcome of the treated patients is needed to better assess the actual meaning of these results . These pilot experiences have probably reduced the interest in controlled clinical trails on the association between thymic hormones and antiretroviral compounds to verify the usefulness of such drugs in the early stages of HIV infection, or in particular phases of the disease in which even s transient increase in the efficacy of the immune response may prove to be helpful . (1) Dardenne M ., Bach J .F ., Safai B . Low serum thymic hormone level in patients with acquired immunodeficiency syndrome . N Engl J Med 1983 ; 309 : 48 . (2) Lazzarin A ., Galli M ., Moriondo P ., Parravicini C ., Poli G ., Moroni M . Increase of OKT4+ cells during treatment with thymostimulin in parenteral drug addicts with persistent generalized lymphadenopathy . J . Clin Lab Immunol 1986 ; 20 : 5761 . (3) Palmisano L ., Chisesi T ., Galli M ., Gritti F .S ., Ielasi G ., Lazzarin A ., Mezzaroma I ., Moroni M ., Raise E ., Vaglia A ., Aiuti F . Thymostimulin treatment in ARC patients . Clin . Immunol . Immunopathol .47,253-261,1988 . (4) Lazzarin A ., Barcellini W ., Uberti Foppa C ., Borghi M .O ., Franzetti F ., Cinque P ., Moroni M . Experiences with immunomodulant agents in HIV infection . Acta haemat 1987 ; 78 (suppl .l) :84-90 .
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Pharmacological Research, Vol. 26, Supplement 2, 1992
THE THYMIC HORMONES IN THE TREATMENT OF IMMUNE DEFICIENCY RELATED TO HIV INFECTION Gianotti N, Finazzi R, Uberti Foppa C, Danise A, Migone T and Lazzarin A . Istituto Scientifico San Raffaele Divisione di Malattie Infettive, Via Stamira d'Ancona, 20 - 20127 Milano Key words : Thymostimulin - Thymopentin - HIV infection The lack of antiretroviral drugs of proven effectiveness during the first years of the spread of AIDS, led to undertake therapeutic trials with drugs potentially capable of stimulating the function of the most compromised cellular network in HIV infection (CD4+ T-lymphocytes) . The aim was to block the progression of the immune deficiency and consequently, to reduce the incidence of opportunistic infections due to cell-mediated immunological defects . Compounds owning to the latter cathegory may include interferons, interleukin-2, isoprinosin, diethyldithiocarbamate, and thymic hormones such as thymostimulin (TP1) and thymopentin (TP5) . Thymostimulin is a natural multifactorial extract of bovine thymus, while thymopentin is a synthetic pentapeptide representing the linear sequence of those five thymopoietin aminoacids which probabily form its active site . The rationale for using thymic hormones in HIV infection, besides the obvious attempt to restore immunocompetence, was based on the evidence of a severe thymic displasia in AIDS patients (1) . Their mechanism of action is still unclear and likely to be complex, as they probably act on the maturation and the differentiation of T-lymphocytes at different levels : within the bone marrow in the phase of switching from stem cell to thymocyte (i .e . on prothymocytes), within the thymus, and within the peripheral lymphatic system . However, it has been argued that thymic hormones could enhance the stimulation of target cells carring an integrated virus, and this might favour the development of latent HIV infection . Moreover, the disappointing results of some pilot studies in patients with full-blown AIDS and AIDS-related complex (ARC), made long term trials with these drugs in the early stages of infection unreasonable . Subsequently, it seemed more rational to associate the standard antiretroviral treatment with immune response modifiers more strictly involved in the HIV-related pathogenetic mechanisms, particulary if at least potentially endowed with antiretroviral activity (interferons, interleukins) . Here we report the results of some our pilot studies with thymic hormones carried out between 1985 and 1986, when antiretroviral drugs of proven effectiveness against HIV were not yet available . The first was conducted in nine case of persistent generalized lymphadenopathy (PGL) treated with thymostimulin 1 mg/Kg/day im for 15 days, and 1 mg/Kg/week the following 45 days(2) . In the treated patients we observed an increase in the absolute number and in the percentage of CD4+ T-lymphocytes during the first two weeks of treatment ; the increase was rapid (within seven days) and accompanied by a parallel augmentation of the CD4+/CD8+ ratio . Nevertheless, these figures returned to basal values six months after the 1043-6618/92/26110062-02/$03 .00/0
© 1992 The Italian Pharmacological Society
Pharmacological Research, Vol . 26, Supplement 2, 1992
beginning of the trial . In the control group a further decrease of CD4+ T-lymphocytes was noticed during the same period . A policentric study of 34 patients treated with TP1 (1 mg/Kg/day for 15 days, and then 1 mg/Kg twice a week for six months) showed a more lasting (up to six months) increase in the absolute number of CD4+ T-lymphocytes, and a higher (though not statistically significant) absolute number of CD4+ T-lymphocytes at the end of the year of observation compared to basal values (3) . These changes in laboratory parameters paralleled a similar improvement of the clinical features, particulary regarding to costitutional symptoms . In a third study, eight patients with PGL were given thymopentin 50 mg three times a week s .c . for three weeks, and 50 mg/week s .c . for three months three months later (4) . In the treated group the absolute number of CD4+ T-lymphocytes and the response to mitogens were significantly increased (p 0,05 and p 0 .01 respectively) ; moreover, at the end of the first cycle, the chemotaxis of neutrophils returned to normal values . The results of these studies show a clearcut, though transient, effectiveness of thymic hormones on improvement of CD4+ T-lymphocytes funtions and absolute number . Nevertheless, a prospective study on clinical outcome of the treated patients is needed to better assess the actual meaning of these results . These pilot experiences have probably reduced the interest in controlled clinical trails on the association between thymic hormones and antiretroviral compounds to verify the usefulness of such drugs in the early stages of HIV infection, or in particular phases of the disease in which even s transient increase in the efficacy of the immune response may prove to be helpful . (1) Dardenne M ., Bach J .F ., Safai B . Low serum thymic hormone level in patients with acquired immunodeficiency syndrome . N Engl J Med 1983 ; 309 : 48 . (2) Lazzarin A ., Galli M ., Moriondo P ., Parravicini C ., Poli G ., Moroni M . Increase of OKT4+ cells during treatment with thymostimulin in parenteral drug addicts with persistent generalized lymphadenopathy . J . Clin Lab Immunol 1986 ; 20 : 5761 . (3) Palmisano L ., Chisesi T ., Galli M ., Gritti F .S ., Ielasi G ., Lazzarin A ., Mezzaroma I ., Moroni M ., Raise E ., Vaglia A ., Aiuti F . Thymostimulin treatment in ARC patients . Clin . Immunol . Immunopathol .47,253-261,1988 . (4) Lazzarin A ., Barcellini W ., Uberti Foppa C ., Borghi M .O ., Franzetti F ., Cinque P ., Moroni M . Experiences with immunomodulant agents in HIV infection . Acta haemat 1987 ; 78 (suppl .l) :84-90 .
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