Immunoregulatory Biological Were Employed to Restore Or Augment the Immune System

Review Paper

Mediators of Inflammation 2, $5-$10 (1993)

WHOLE bacteria or bacterial components or their extracts Immunoregulatory biological were employed to restore or augment the immune system. Beneficial effects were attained with these agents in response modifiers" effect of treating various diseases. These agents were named cytokines on septic shock biological response modifiers (BRMs) because they regulated certain cellular components of the immune system. The cellular regulation induced by these BRMs Michael A. Chirigos1"cA and was found to be due to cytokines. The cytokines were 2 shown to act directly on the various cellular components Claudio De Simone and to provide therapeutic benefit in various autoimmune and immune deficiency diseases. Overproduction of specific cytokines however leads to a deleterious effect on National Cancer Institute, National Institute of the host. Overproduction of tumour necrosis factor Health, Bethesda, MD, USA; 2Infectious (endotoxin, lipopolysaccharide) leads to septic shock. Diseases, Department of Internal Medicine, Bacteraemia is the leading cause of overproduction of University of L'Aquila, L'Aquila, Italy tumour necrosis factor (TNF). Septic shock in many cases leads to death. Several monoclonal antibodies to lipopolysaccharide (LPS) and anticytokines have demonstrated CACorresponding Author- 4 Cold Spring Court, protection against septic shock. Potomac, MD20854, USA Key words: Biological response modifiers, Cytokincs, lntcrlcukins, Scptic shock, Tumour necrosis factor

A little over 25 years ago the concept of use for various diseases is shown in Tables 7 to 11. introducing an exogeneous substance to elicit a host Table 7 shows that the use of BCG increased the immune response was limited to such agents as various cellular responses" T-cells, macrophages bacterial organisms (Table 1), to be followed a few (MPG), natural killer cells (NK), and cytotoxic years later by the use of partially purified microbial T-lymphocytes (CTL). The cytokines induced by extracts or fractions (Table 2). The use of these BCG are interleukin 1 (IL-1), IL-2, interferon alpha microbial agents to stimulate the immune response (IFN-), granulocyte-monocyte colony stimulating gave way to the use of chemically defined BRMs factor (GM-CSF), and turnout necrosis factor (Table 3), and to extracts from yeast, fungi, plants (TNF). Treatment with BeG alone, or combined and herbs (Table 4), and polysaccharidcs (Table with other treatment modalities (chemotherapy, 5). 1'2 surgery, irradiation), resulted in beneficial responses During the past 15 years, as the result of progress in several animal and human cancers. BCG made in molecular biology, the immunoregulating effects attributed to the aforementioned BRMs were Table 2. Biological response modifiers of biological origin found to be due to cytokines that were induced and secreted by cells responding to these BRMs (Table Microorganisms (complete or partially pure extracts) 6). The capacity of several of these BRMs to regulate Picibanil (0K432, Streptococcus pyogenes) MER (methanol extracted residue, BCG) a specific cell population and/or induce the MY-1 (extract BCG) production of a specific cytokinc and its therapeutic RU41740 (Biostim, glycoprotein, K. pneumoniae) Mycolic acid (glycolipid, Nocardia rubra) Bru Pel (Brucel/abortus) MDP (muramyl dipeptide, Mycobacterium smegmatis) Table 1. Biological response modifiers of biological origin WSA (disaccharide peptoglycan, Mycobacterium smegmatis) CWS (cell wall skeleton, BCG, Nocardia rubra) Microorganisms (bacterial preparations) Forphenicino (Aspergillus fulvoviridis) GBA (amino sugar polymer, cytophaga) Bacillus Calmette-Guerin (BCG) Haemophilus influenza BV (Broncho Vaxom, alkaline lysis extract of eight bacterial Corynebacterium parvum Streptococcus pyogenes mixtures) Brucella abortus S. aureus, S. viridans Imuvert (ribomes and membrane vesicles of Serratia marcescens) Bordetella pertussis Neisseria catarrhalis Detox (detoxified endotoxin) Nocardia rubra Salmonella typhimurium OM-89 (purified E. coli extract) Pseudomonas aeruginosa Listeria moocytogenes CVE (glycoprotein, H20 extract of Chlorella vulgaris) Chlorella vulgaris Streptom yces folvoviridis SSG (fl 1,3 glucan, Sclerotinia sclerotiorum) Klebsiella pneumonia Serratia marcescens Other fungal extracted fl 1,3 glucans (sonifilan, sizofiran, Diplococcus pneumonia Chlorella vulgaris grifolan)

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Table 3. Chemically defined biological response modifiers Table 5. Polysaccharide biological response modifiers

Amphotericin B HAB 439 Splenopentin (DAcSP-5) AM3 Azi mexon muth iol S PG fl-1,6, polyglycan protein ADA 202-718 Indomethacin THF 2 Candida albicans) ABPP Isoprinosine TOK 8801 A 171-172 LF 1695 Thymopentin Betafectin Bestatin L 646,257 Tuftsin poly (1,6) fl-g-glycopyranosyl-(1,3) fl-g-glucopyranose Betafectin Levamisole Therafectin (SM 1213) Saccharomyces cerevisiae) Cimetidine Lipidal amines Thiazolobenzimidazole Curdlan sulphate (CS) CL 246,738 MDPs Thiobendazole sulphated fl-1, 3-o-glucopyranan CL 259,763 MPG IFN inducers: DT 5461 MIMP Poly IC Glucan EL-l, EL-2 Pyrimidinols Poly ICLC /-1, 3 glucose Formosanin-C Retinoids Poly AV Saccharomyces cerevisiae) Forphenicinol Ricin Ampligen FK 506, FK 565, SM 8849 Anthroquinones GBA FK156 SDZMRL953 RP40639 Pimelantide N-acetyl glucosamine RU 41740 (Biostim) Oxamisole Cytophaga bacterium) Lentinan fl-l,3-glucan, 1-6-/t-D glucopyranoside Lentinus edodes, mushroom) treatment of human transitional cell carcinoma of PSK (Krestin) the bladder led to greater than 90% regression with protein bound polysaccharide Coriolus vesicolor, minimal recurrence. More recently local/regional mushroom) immunotherapy with IL-2 was reported to also RBS (RON) glucan mediate regression of this tumour type. This derived from rice bran response demonstrates that the cytokine inducer RU41740 (Biostim)-MPG (BCG), as well as the BCG induced cytokine (IL-2) glycoprotein extract were both therapeutically effective against the same Klebsiella pneumoniae) tumour. SDZ MEL 953 OK 432 (Table 7) has had extensive preclinical synthetic acylated glucosamine-monosaccharide-1 -PO, 4-6 and clinical evaluation and has been shown to be SSG beneficial in treating various cancers. Similarly, fl-1,3 g glucan Lentinan has shown eflqcacy in augmenting immune Sclerotinia sclerotioram, fungus) restorative activity beneficial for treating various Sizofiran infections. 4 Tables 8 to 11 describe several BRMs fl-polyglucan of bacterial, thymus, and polysaccharide origin Schizophylum commune) which exert immunoregulatory activity. SPG 1,3 to fl- glucan Swainsonine (Table 11) was recently reported (Sulphated Schizophylum) cause a marked elevation in superoxide radical Sonifilan /% 1,3 glucan (fungal extract) Table 4. Extracts from yeast, fungi, plants and herbs SPR 901 Extracts isolated from yeast or fungi 1,6 glucan Leuconostoc mesenteroides) Krestin (PSK, protein bound polysaccharide, Coriolas versicolor) Glucan 1,3 polyglucose, Saccharomyces -WSA (beta cerevisiae) Lentinan (beta 1,3 polyglucose, Lentinus edodes) disaccharide bound to peptidoglycan Cyclomunine (cyclohexa peptide, Fusarium equiset) M. smegmatis) Bestatin (2S, 3R-amino-2-hydroxy-4-phenylbutanoyl-L-leu- cine, Streptomyces olivoreticulO Schizophyllan (beta 1,3 polyglucose, Schizophyllum commune) SPG (sulphated schizophyllan) FK156 and FK565 (tetrapeptides, Streptomyces olivaceo- griseus) Table 6. Interrelationship of biological response mod- AM-3 (protein complexed beta 1,6 polyglucan, Candida utilis) ifiers to cytokines

Plant and herb extracts Synthetic, biological, polysaccharides, herbs Ace mannan (Carrisyn, Aloe vera barbadensis) Bryostatin (macrocyclic lactones, marine plant Bryozoan bugula Primary cell receptors meritina) RBS (RON) (-glucan derived from rice bran) Cytokine induction Formosanin-C (diosgenin saponin, Paris formosana hayata plant, Liliaceae) Monocytes Lymphocytes Ginseng (Panax ginseng, Araliaceae) (Monokines) (Lymphokines) Huang-chi (Astragalus membranaceus, Leguminosae) Shosaiko-To (Xiao-Chai-Hu-Tang, seven herb mixture) Cytokines

S6 Mediators of Inflammation. Vol 2 (Supplement). 1993 Immunoregulatory biological response modifiers

Table 7. Characterization of biological response modifiers Table 9. Biological response modifiers of thymus and various relative to cell regulated, cytokine and disease treatment origin

Bacterial Thymomodulin (TMD), thymolymphotropin (TLT), thymic BCG derivatives containing several peptides CR" T T-cell function, macrophage (MPG), NK, CTL CR: NK, T, B, MPG CK: IL-1, IL-2, IFN-, GM-CSF, TNF CK: IFN-, IL-2, BCGF, GM-CSF TR" +murine antitumour effect-t-adjuvant therapy; human TR: TCD4 in AIDS; 120 mg/kg/day per o.s. for'30 d in acute recurrent superficial bladder tumours, transurethal resection and type B hepatitis led to accelerated AST, ALT decrease, early H Bs intravesical BCG leads to greater than 90% response, absence Ag clearance and normalization of elevated cDg; a 50% sero of recurrence. conversion of pediatric HBs Ag + H-Be Ag + chronic liver disease; and, protection vs bone marrow depression during 0K432 (Pecibinil) Streptococcus pyogenes, strain A3 intensive antitumour chemotherapy. CR:I" T-cell function, MPG, NK, CTL, TIL CK: IL-1, IL-2, IFNT, TNF Betafectin--poly 1,6 fl-D-glucopyranosyl/1,3,fl-D glucopyr- TR" +murine antitumour; increase survival time and disease anose (glucose polymer); Saccharomyces cerevisiae RAD2. free interval in human colo-rectal, cervical, lung Ca" I'NK, CR: 1" MPG, NK, BM M PG, T-cells in malignant ascites. CK: IL-1, IFN TR: Protects vs E. coli peritoneal sepsis, Candida albicans, S. Lentinan (1,3, fl-g-glucan" 1,6-fl-g-9-glucopyranosides), Len- Aureus, lethal irradiation LD9o. Mechanism binds to fl-glucan tinus edodes receptors on Mo, PMN, which enhance phagocytic and CR" NK, MPG, T, bone marrow microbicidal activity. CK: IL-2, IFN, CST TR" + vs murine tumours, increase in ST, duration of remission AM-3protein complexed B1,6, polyglucan, Candida utilis of human CA, 1"efficacy with chemical prophylactic vs CR: NK, T, MPG, bone marrow influenza" Mesocestoides corti prophylactis. CK: IL-1, IL-2, IFNfl, CSF TR: + vs mrrine turnout and viral infection; combined with CR cell response" CK cytokines" TR therapeutic response. chemotherapy led to earlier reconstitution of bone marrow, decrease in secondary infections.

CR cell response; CK cytokines; TR therapeutic response. production and induction of TNF-0 secretion from macrophages, Of particular interest is swainsonine's protective effect against bone marrow depres- Another example of the similarity in responses sion resulting from treatment with the chemother- achieved by BRMs and the cytokines they induce apeutic agents methotrexate (MTX), 5-fluorouracil is shown in Table 12. Ampligen and CL246,738 are (5-FU), cyclophosphamide (CP), or doxorubicin potent interferon inducers. Their antiviral effects (DOX). were compared to recombinant IFN gamma Thymosin fraction 5 (THF 5) when combined (rlFN-2) and rIFN- against four virus types. All with thymosin alpha for the treatment of chronic four agents augmented NK cell activity as well as hepatitis B led to clearance of the virus and activating macrophages. An antiviral correlation improved liver function. was shown among all four against three of the four- viruses. Cytokines (Table 13) are increasingly recognized as essential and powerful cell communication and Table 8. Biological response modifiers of bacterial origin

Bacterial extracts Table 10. Biological response modifiers of various origin RU41740 (Biostim, MPG) membrane protein extract of K/ebsie//a pneumonia C R: T, M PG, N K, polyclonal B Synthetics CK: IL-1, IL-6, GM-CSF Oxamisole--2,3,5,6,7,8 hexahydro 2 phenyl 8,8 dimethoxy- TR: prevents bacterial respiratory infection imidazole [1,2,] pyridine FK 156, 506, 565: original 156 isolated from fermentation broth CR: NK, ADCC of Streptomyces FK 156, 565 CK: IL-1, IL-2 CR: T, NK, MPG TR: effective vs murine hepatitis (FB strain) decreased hepatic CK: IL-1, CSF discoloration, SGOT, SGPT, virus titre in liver TR: +murine tumours, antiviral (antibacterial) Ampligen--mds RNA Treatment Dose#g/kg NK Cytot. 100:1 No. lung mets; B16 CR: NK, MPG, CD4 Saline 10.1 287 CK: IFNfl, CSF FK565 0.01 9.9 307 TR: + vs murine tumours; inhibits AZT sensitive and resistant 0.1 34.3 62 HIV-1, protects vs AZT bone marrow toxicity, increased CD4 1.0 29.0 9 count in treated AIDS patients. FK506: immunosuppressor: mechanism is considered to HAB439--3 phenyl-2-isoxazoline-5-yl phosphoric acid operate during the first signal transduction cascades and CR: T, NK ultimately blocks the transcription of the genes that encode IL-2 CK: not known and other lymphokines. Reported effective in treating psoriasis, TR: may act through an aminopeptidase inhibitor; inhibits organ rejection, nephrotic syndrome, Type diabetes (insulin- Listeria monocytogenes, Salmonella typhimurium, synergistic dependent juvenile diabetes). with ampicillin.

CR-cell response; CK cytokines" TR therapeutic response. CR cell response; CK cytokines" TR therapeutic response.

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Table 11. Current applications of biological response modifiers Table 14. Cytokines and their applications

Swainsonineindolizidine alkaloid EPO (Erythropietin). Regulates RBC production. Used for CR: NK, MPG, bone marrow treating anaemia (reduces or eliminates blood transfusions in CK: IL-1, IL-2 kidney dialysis patients, AIDS, cancer). TR: protects vs drug induced bone marrow suppression, LD9o G-CSF (Granulocyte Colony Stimulating Factor). Stimulates doses MTX, 5FU, CP, DOX combined with drug led to granulocyte formation, adjuvant use to overcome leukopenia stimulation of bone marrow. developing after chemotherapy. Thymosin--thymosin fraction 5 + thymosin alpha 1. GM-CSF (Granulocyte-Macrophage Colony Stimulating Fac- TR: treatment of chronic hepatitis B (phase II). Patients (20) tor). Stimulates production and function of activities of enrolled; histological and biochemical evidence for active liver granulocytes and macrophages. Uses are similar to G-CSF. disease with + serum hepatitis B virus (HBV) DNA + hepatitis IL-2 (Interleukin 2). Stimulates production and function of B surface antigen (HBsAg). Rx, 2x/week, 6 months sc. At T-cells, N K cells. Use in treating renal cell carcinoma, melanoma. year: 9/12 thymosin treated and 2/8 placebo showed normal Potential synergy with alpha FN; uses in infection and vaccine serum alanine aminotransferase (ALT) and cleared (HBV) DNA adjuvant. from serum (p<0.04). From twelve available pre- and post-treated liver biopsies; 4/5 placebo and 1/7 thymosin Rx Alpha Interferon. Approved in 50 countries for 16 indications livers possessed replicative forms of (HBV) DNA. including cancer, AIDS, hepatitis. Beta Interferon. Similar clinical properties to alpha-IFN. Being CR cell response" CK cytokines; TR therapeutic response. tested for viral diseases and multiple sclerosis. Gamma Interferon. Potential uses in cancer, infectious diseases, ectopic dermatitis, rheumatoid arthritis. Table 12. Antiviral--in vivo responses TNF (tumour necrosis factor), rTNF used in limited clinical trials as potential anti-cancer agent. BRM NK MPG VEE BANZI HSV2 Caraparu rlFN-2 + + + + NT rlFN-c + + + + + NT The field of cytokine is Ampligen 4- + --I- + biology growing rapidly. CL246,738 + + + + + Studies are being conducted that embrace analysis of molecular regulation of cytokine expression VEE Venezualen equine encephalitis (alpha toga virus)" through the use of cytokines per se as therapeutic BANZI (flavivirus)" Caraparu (bunyavirus). +positive response" no response" NT not tested. agents. Diseases that involve employing cytokines include cancer, infectious diseases, inflammatory processes, autoimmune disorders, physiological regulatory molecules. They are implicated in development defects, and ageing. Cytokines appear normal homeostasis and defence against many to extend in some fashion to every organ system of diseases and are involved in the pathogenesis of a the body. Of particular interest is the potential use variety of disorders. As a result of their powerful of cytokines in the treatment of cancer, where they and widespread regulatory functions, a number of are being tested as direct anti{umour agents, as cytokines are being tested as therapeutic agents enhancers of various cellular components of the (Table 14). At the same time, many antagonistic immune system reactive against tumour cells, as factors are being developed for use in those diseases potentiators of chemotherapy and radiotherapy, and that may be initiated or mediated by cytokines. as protective agents against the myelotoxicity

Table 13. Cytokines derived from monocytes/macrophages (monokines) or lymphocytes (lymphokines)

Cytokine Primary cell source Primary effects

L-1 Macrophages, keratinocytes, Inflammatory, haematopoietic endothelial cells, fibroblasts, T, B L-2 T-lymphocytes and LGL Activates T- and N K cells L-3 T-lymphocytes Promotes myeloid progenitor cells L-4 Th cells T-, B-cell growth factor, promotes IgE L- 5 Th cells Stimulates B-cells, eosinophils L-6 Fibroblasts, other Growth factor B-cells, polyclonal IG L-7 Stromal cells Lymphopoietin, generates pre-B, T L-8 Macrophages, other Regulates lymphocyte, neutrophils, homing, infiltration, chemo attracts G-CSF Monocytes, other Myeloid growth factor, generates neutrophils M-CSF Monocytes, other Macrophage growth factor, macrophages G M-CSF T-cells, other Monomyelocytic GF, myelopoiesis FN- Leucocytes Stimulates macrophages and NK cells IFN- Fibroblasts Stimulates macrophages and N K cells IFN-7 T- and NK cells Induces cell membrane Ag (,MHC) TN F Macrophages, other Vascular thromboses, tumour necrosis TN Ffl-LT T-lymphocytes and inflammatory, immunoenhancer TNFfl Platelets, bone, other Wound healing, bone remodelling, fibroplasia, immunosuppressor

S8 Mediators of Inflammation. Vol 2 (Supplement)-1993 Immunoregulatory biological response modifiers

Table 15. Mediators of natural immunity

Cytokine Cell source Cell target Primary effects

Type FN Mononuclear phagocyte (a), fibroblast (b) All Antiviral, a nti prol ferative; increases class M H C expression Tumour necrosis factor Mononuclear phagocyte, T-cell N eutrop h I, Act ivat on endothelial, (inflammation), hypothalamus, activation liver, muscle, (coagulation), fat, T-cell, B-cell fever, acute phase reactants, catabolism (cachexia), costimulator Interleukin Mononuclear phagocyte, other T-cell, B-cell, Costimulator, endothelial cell, antiviral hypothalamus, (inflammation, liver, muscle, fat coagulation), fever, acute phase reactants, catabolism (cachexia) Interleukin 6 Mononuclear phagocytes, T-cell, endothelial cell T-cell, B-cell, Costimulator, mature B-cell, growth, acute liver phase reactants MIP-1 Mononuclear phagocytes N eutroph Is, Cost im u lator, macrophages, activation- hypothalamus (inflammation), costimulator (induced TNF) IL-1, IL-6 production), fever

associated with current cancer treatments. In homeostasis and health, but at other times the contrast to their potential therapeutic value, some overproduction of immunoregulatory mediators cancer cells produce cytokines which may be may actually prove deleterious to the host. Some involved in autocrine growth stimulation. examples of immune system mediated injury have Cytokines have been classified into four categor- been extensively investigated including anaphylac- ies: tic shock, autoimmune disease, and immune complex disorders. More recently it has become Mediators of natural immunity consisting of clear that the cytokine TNF a role in Type 1 IFN, TNF, IL-1, IL-6, and low occupies key the pathophysiology associated with diverse inflam- molecular weight inflammatory cytokines to states and other serious illnesses which the MIP-1 matory including recently reported may shock. TNF exhibits beneficial and deleter- belong, septic ious functions when combined with adriamy- (2) Mediators of lymphocyte activation, growth, cin. TNF demonstrated an enhanced cytotoxicity and differentiation consisting of IL-2, IL-4 and several resistant human tumour transforming growth factor beta against adriamycin (TGF-fl). lines. A similar synergistic enhancement of (3) Mediators of effector cell activation consisting adriamycin cytotoxicity against human osteosar- of IFN-,, lymphotoxin, IL-5, and migration coma cells TNF-z was also 1 inhibition factor by reported. (MIF). In several indicate that TNF (4) Mediators of immature leucocyte growth and contrast, reports also possesses deleterious Recombinant differentiation consisting of IL-3, GM-CSF, properties. TNF functioned as an autocrine factor M-CSF, G-CSF, and IL-7. growth which enhanced growth of four human neuro- Mediators of natural immunity are the host's blastoma cell lines. 1 Blocking factors (soluble more initial and immediate responders since they receptors) for human TNF and lymphotoxin (LT) initiate protection against viral infection. They were found in the serum, cerebral spinal fluid, and initiate inflammatory reactions that protect against tumour cyst fluid (TCF) of human glioma tumour bacteria (Table 15). In some cases this complex patients. 2 The presence of these receptors would defence network successfully restores normal abrogate any tumour cytolytic activity of TNF or

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Table 17. Potential treatments for septic shock Table 16. Tumour necrosis factor leading to septic shock

Early attempts The most prominent bacterial infections are E. coli, P. 1980s Treatment with human antisera to E. coli J5, a mutant aeruginosa, Klebsiella and Bacteroides. When these are present strain producing LPS with variable oligosaccharide. Of 212 in blood (bacterial sepsis), levels of TNF increase, and autocrine bacteraemic patients treated 50% survived. and paracrine effects increase L-1 and L-6. The combined Drawbacks to antiserum--heterologous pool of sera, standard- effect ization difficulty, serum contaminated with infectious agents. Leads to depressed myocardial contractility (reduces 1985 Monoclonal immunoglobulin M (IgM) binding specific- tissue perfusion). ally to the lipid A domain of LPS. Comparative study: 2 Relaxes vascular smooth muscle tone (leads to a reduction 1. Standard therapy and antibiotics and fluids, 49% died. of blood pressure and tissue perfusion). 2. Standard therapy and m,Ab to lipid A, 30% died. 3 Causes intravascular thrombosis. 1990s 4 Causes severe metabolic disturbances (life threatening fall 1. IL-lra (IL-1 receptor antagonist). Natural protein antagonist in blood glucose concentrations). of IL-1, competes for IL-1 receptor (Antril). 5 Leads to a spontaneous clotting in blood vessels, severe 2. IL-lr (interleukin receptor). Competes with the natural hypotension, multiple organ damage (mostly due to IL-1 receptor to down-regulate IL-1. circulatory collapse and oxygen free-radical damage). 3. Anti-TNF mkb (antitumour necrosis factor antibody). The rate of occurrence of septic shock following septicaemia is Blocks TNI mediated damage in sepsis, cachexia, etc. 175 per 100 000 people yearly, and 500 per 100 000 for patients 4. TNF inhibitors (tumour necrosis factor inhibitors). Natural in hospitals. Of those that develop septic shock, 25 to 40% die. protein inhibitors of TNF that might limit systemic damage in septic shock. 5. TNFr-Fc (TNF receptor immunoadhesion). Soluble TNFr mediated immune linked to Fc region of m,Ab. Potential use in sepsis. interrupt the cytokine response 6. Sepsis mAb. Monoclonal antibodies vs Gram-negative to septicaemia, while the other group targets LPS, bacterial endotoxin for treatment of sepsis syndrome and either to neutralize it in the blood or to prevent it septic shock. from that start the inflam- 7. BPI (bacterial permeability increasing protein). Neutrophil activating leucocytes granule protein, blocks Gram-negative endotoxin; inhibits matory response. The latter approach however TN F, L-6 and L-8 cytokines. would function for Gram-negative sepsis only. 8. Other drugs: pentoxiphylline; L-carnitine derivatives. References 1. Chirigos MA, Talmadge JE. Immunotherapeutic agents: their role in cellular immunity and their therapeutic potential. Springer Semin Immunopathol LT. Similar TNF growth promoting activities were 1985; 8: 327-346. 13 reported for ovarian cancer and perhaps for 2. Talmadge JE, Chirigos MA. Comparison of immunoregulatory and 14 immunotherapeutic properties of biological response modifiers. Semin mammary tumour cells. Colony growth of Immunopathol 1985; 8: 429-443. leukaemic colony-forming units (L-CFU) obtained 3. Velotti F, Cippitelli M, Palmieri Get al. In vitro bladder cells express acute interleukin 2 receptor. AACR Proceedings 1992; 33: 301. from patients with primary myelogenous 4. Chirigos MA. Immunomodulators: current and future development and leukaemia stimulated with recombinant human IL-3 applications. Thymus 1992; Suppl 1: $7-$20. 5. Ishida N, Hoshino TA. Streptococcal preparation potent biological (rhlL-3) was reported to be significantly potentiated response modifier (OK432). Exerpta Medicus (second edn) 1985; 1-69. when recombinant human TNF-0 was present in 6. Chirigos MA, Saito T, Talmadge JE, Budzynski W, Gruys E. Cell regulatory 15 and immunorestorative activity of Ricibanil (OK432). Cancer Detect Prevent the culture. Studies on the mechanism of action Suppl 1987; 1: 317-320. of rhTNF-0 on the acute myelogenous leukaemia 7. Gryegorgewski K, Breton P, White S, Olden K. Eect of swainsonine acts murine peritoneal macrophages in vitro superoxide radical production, L-CFU growth suggests that TNF- by phagocytosis, kinetics of activation, and TNF alpha production. AACR inducing release of growth stimulating haemato- Proceedings 1992; 33: 304. 8. Sherry B. The role of cytokines in the regulation of cell function and in the poietic cytokines by the leukaemic cells themselves pathogenesis of disease: pathology A--B study section workshop. Cancer including IL-I, IL-lfl, GM-CSF, G-CSF, and Res 1992; 52: 6129-6133. to 9. Safrit JT, Bonavida B. Sensitivity of resistant human tumor lines to tumor IL-6. Treatment with neutralizing antibody all necrosis factor and adriamycin used in combination: correlation between of the above cytokines significantly inhibited the down regulation of tumor necrosis factor messenger RNA induction and of TNF-0 and IL-3. The role overcoming resistance. Cancer Res 1992; 52: 6630-6637. synergistic interplay 10. Jia SF, Fara D, Kleinerman ES. Synergistic enhancement of adriamycin of TNF leading to septic shock is illustrated in cytotoxicity against human osteosarcoma cells by TNF-. AA CR Proceedings 1992; 33: 552. Table 16. 11. Goillot E, Combaret V, Landenstein R et al. Tumor necrosis factor (TNF) Advances in cytokinology and molecular biology autocrine growth factor for neuroblastomas. AA CR Proceedings 1992; 33: 346. develop in such a way that multiple approaches 12. Ioli G, Yamamoto R, Jacques D et al. Blocking factors (soluble receptors) emerge to attack a problem. That has happened for for human TNF and I,T in the serum, cerebrospinal fluid (CSF), and tumor cyst fluid (TCF) of human glioma patients. AA CR Proceedings 1992; 33: 309. septic shock, a frequently fatal reaction following 13. Naylor MS, Stamp GW, Foulkes Wet al. TNF (tumor necrosis factor). A bacterial infection leading to a bacteraemia. Using role in ovarian cancer? AACR Proceedings 1992; 33: 262. re- 14. Tsai Sj, Miller J, Wei WZ et al. Tumor necrosis factor (TNF) modulates recent advances in cytokine biology and growth of normal and neoplastic murine mammary cells. AA CR Proceedings combinant DNA technology immunologists and 1992; 33: 269. are six 15. Brock MA, Gruss HJ, Asano Y et al. Synergy of interleukin and tumor molecular biologists currently evaluating necrosis factor alpha in stimulating clonal growth of acute myelogenous 16 potential new treatments for septic shock. leukemia blasts is the result of induction of secondary hematopoietic who shock fall into cytokines by tumor necrosis factor alpha. Cancer Res 1992; 52: 6129-6133. Investigators study septic 16. Johnston J. Molecular science gets its sights septic shock. J NIH Research two categories (Table 17). One group works to 1991 3(10): 6i-65.

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