Joseph Eldor, MD
Theoretical Medicine Institute
PO Box 12142, Jerusalem, 91120, Israel
Cancer cells release various antigens, some of which appear in the urine. Oral auto-urotherapy is suggested as a new treatment modality for cancer patients. It will provide the intestinal lymphatic system the many tumor antigens against which antibodies may be produced. These antibodies may be transpierced through the blood stream and attack the tumor and its cells.
The Philosophy of Cancer
Microbes were known long before the germ theory of disease was invented. It was not the discovery of germs that revolutinized medicine, but the invention of a philosophy of medical explanation that permitted germs to be causative agents of disease(1). Burnet and Thomas(2) postulated that specific cell mediated immunity may have evolved in vertebrates specially for defense against the "enemy within" rather than against infecting microorganisms and parasites. Most human cancers appear to lack truly tumor-specific antigens. The same neoplastic cell can express several different tumor antigens. For example, relatively cross-reacting tumor-specific transplantation antigens have been demonstrated in many chemically induced tumors(3). Tumor-associated differentiation antigens are shared by neoplastic and embryonic cells(4). The extent to which human patients react immunologically against their cancers has been a subject of much controversy(5). Paul Ehrlich, in 1909, said: "I am convinced that during development and growth malignant cells arise extensively frequently but that in the majority of people they remain latent due to the protective action of the host. I am also convinced that this natural immunity is not due to the presence of antimicrobial bodies but is determined purely by cellular factors. These may be weakened in the older age groups in which cancer is more prevalent"(6).
Tumor Antigens in Urine
Human melanoma cells express membrane antigens distinct from those of the normal ectodermal counterparts(7). Urinary-tumor-associated antigen (U-TAA) is one such antigen. This high-molecular weight glycoprotein was first described when melanoma urine was found to react with autologous antibody(8). The antigen has since been detected in the urine of 68% of melanoma patients. In addition, high levels of U-TAA are found to correlate positively with disease occurrence in surgically treated patients(9). Prostatic specific antigen (PSA) has become an important laboratory test in the management of prostate cancer. PSA levels can be as readily obtained from voided urine as from serum samples(10).
Quantitative urinary immunocytology with monoclonal antibody (mab) 486p 3/12 proved to be valuable for diagnostic use in bladder-cancer patients' urine, especially in the follow-up of patients with superficial bladder carcinoma(11). Quantitative urinary immunocytology is a general tool to test the diagnostic usefulness of mabs, assuming that normal and malignant cells differ in their quantitative expression of a given antigen. Selective criteria for selecting mabs for diagnostic approaches should ask not for tumor specificity, but for different quantitative expression of antigen in the tissues or cells in question Gastric juice oncofetal antigen determination, due to direct shedding of antigens into the fluid around tumor tissues, appears to accurately indicate the presence and degree of gastric mucosal damage and to be to a slight extent influenced by unrelated factors(12). Patients` age, for example, modifies CEA serum levels(13). A monoclonal antibody (mab) against a human colorectal adenocarcinoma cell line has been raised(14), which reacts with sialosylfucosyllactoteraose(15) corresponding to the sialylated blood group antigen Lewis (a). The antigen defined by this antibody, CA50, is elevated in the serum of many patients with gastrointestinal tumors(16), with a sensitivity for gastric cancer ranging from 20(17) to 65%(18). CA50 (a tumor-associated gangliosidic antigen) levels have been determined by an RIA test in serum, gastric juice and urine of patients undergoing upper gastrointestinal tract endoscopy. Sensitivity and specificity were respectively 23% and 89% for CA50 determination in urines(19).
Soluble forms of membrane proteins such as cytokine receptors or cellular adhesion molecules (CD14, TNF receptor, CD25, IL-6 receptor, IFN-ç-receptor and CD54) have been detected in human body fluids. They may have important functions in immune regulation by blocking receptor/ligand interactions. The human adhesion receptor CD58 (LFA-3) is expressed on most cell types. A soluble form of CD58 (sCD58) was purified from human urine and partially purified from supernatant of the Hodgkin-derived cell line L428(20). Urinary organ-specific neoantigen from colorectal cancer patients has been used to make a monoclonal antibody, BAC 18.1(21). Organ-specific neoantigen originates in the colon and is excreted into the urine, so the BAC 18.1 binding levels in the urine may be a diagnostic aid for colorectal cancer. The polyamines spermidine, spermine and their diamine precursor putrescine are ubiquitous constituents of mammalian cells that are fundamentally involved in normal, malignant and induced proliferative states. The polyamines and ornithine decarboxylase (ODC), the rate-limiting enzyme of the polyamine metabolism, were found to play an important role in tumor promotion(22). The suggestion that polyamines play an important role in colorectal cancer was confirmed by studies that found elevated polyamine concentrations in blood or urine(23) of patients with colon carcinoma.
Sensitivity of urinary polyamines for colon cancer were highest for total spermidine (92.1%), acetylated putrescine (84.5%), total putrescine (84.0%), N1-acetylspermidine (79.3%) and N8-acetylspermidine (78.6%), but in all these cases specificity was lower than 65%(24). In patients with successful curative surgical treatment all preoperatively elevated urinary polyamine concentrations markedly decreased and returned to normal, whereas they were elevated and increased further in patients with proven relapse of the tumor and/or metastases in different organs(24).
The function of the CD44 gene is severely damaged, beginning with the very early pre-invasive stages of tumor development. This can be used as a means of tumor detection and diagnosis both on solid tissue specimens(25) and on exfoliated cells in clinically obtained excreta and body fluids(26). Urine cell lysates obtained from patients with bladder cancer can be discriminated from normal urine lysates(27) using Western blotting with a monoclonal antibody against the standard form of the CD44 protein.
Zbar and Tanaka(28) first reported on animal immunotherapy based on the principle that tumor growth is inhibited at sites of delayed hypersensitivity reactions provoked by antigens unrelated to the tumor. They injected living Mycobacterium bovis (strain BCG) into established intradermal tumors and caused tumor regression and prevented the development of metastases. For optimum therapeutic effect contact between BCG and tumor cells was necessary. The ability of tumor immune lymphocytes to localize specifically to tumor offers a possibility for therapy which has been utilized over the past several years(29). The rejection of murine tumors expressing tumor-specific transplantation antigens has been shown to be mediated primarily by immune cells(30). Some 6 to 7% of transplant recipients may develop cancer as a consequence of iatrogenic immunosuppression(31).
Studies on the ability of patient lymphocytes to lyse tumor cells in short term (2-8 hr) isotope release assays have shown that lymphocytes from cancer patients can generally destroy only tumor cells from the same patient(32,34), unless the effector cells are not cytolytic T cells but, for example, Natural Killer cells or Lymphokine Activated Killer cells, in which case neoplastic cells representing many different types are sensitive.
Immunotherapy is believed to be capable of eliminating only relatively small amounts of neoplastic cells and, therefore, the failure to induce a regression in patients with excessive tumor burden is not unexpected(35,36). One approach of immunotherapy is to "xenogenize" tumor cells by virus infection. Another is to culture tumor infiltrating lymphocytes with interleukin-2 and reinoculate them into the host with cytokines(37). The introduction of recombinant vectors expressing cytokine genes into tumor infiltrating lymphocyte cells(38) or into the tumor cells themselves(39) may enhance the migration of effector immune cells into the tumor with consequent immunomediated control. The considerable heterogeneity in the expression of tumor associated differentiation antigens by cells within the same tumor constitutes a problem for any immunotherapy, since it facilitates the escape of antigen-negative tumor variants.
An alternative approach toward increasing the immune response to tumor-associated differentiation antigens is to treat the host to be immunized so as to abolish a "suppressor" response. Such treatment can be provided in the form of sublethal whole body x-irradiation(40), injection of a drug such as cyclophosphamide(41), or by the administration of certain anti-idiotypic antibodies(42).
Anergy is defined as a state of T lymphocyte unresponsiveness characterized by absence of proliferation, IL-2 production and diminished expression of IL-2R(43,44). Most available data support suppression as a mechanism of oral tolerance(45,46). Immunological suppression is classically demonstrated by the suppression of antigen-specific immune responses by T lymphocytes(47,48).
Oral administration of S-antigen (S-Ag), a retinal autoantigen that induces experimental autoimmune uveitis, prevented or markedly diminished the clinical appearance of S-Ag-induced disease as measured by ocular inflammation(49,50).
Gut associated lymphoid tissue has the capacity to generate potent immune responses on one hand, and to induce peripheral tolerance to external antigens on the other(51,53). Both processes require antigen stimulation(53), involve cytokine production(51) and might occur at the same time―the first leading to potent local and systemic immune responses, while the latter leads to systemic antigen―specific nonresponsiveness(54). The generation of acquired immune responses in the small intestine is believed to occur in Peyer`s patches(51,55).
Orally fed protein antigens are found in the blood within 1 hr of feeding(56). Peripheral tolerance is not induced locally, but rather is induced systemically upon transfer of intact antigen, or its peptides, into the circulation(57,59).Oral tolerance may be induced by a single feeding of a protein antigen(60,61) or by several intermittent feedings(46,62). In order to test whether feeding on autoantigen could suppress an experimental autoimmune disease, the Lewis rat model of experimental autoimmune encephalomyelitis was studied(63). With increasing dosages of GP-MBP, the incidence and severity of disease was suppressed, as well as proliferative responses of lymph node cells to MBP. Antibody responses to MBP were decreased but not as dramatically as proliferative responses. Thus it appears that oral tolerance to MBP, as to other non-self antigens(45), preferentially suppress cellular immune responses. It appears that homologous MBP is a more potent oral tolerogen for experimental autoimmune encephalomyelitis than heterologous MBP(64).
Tumor cells may escape immune recognition in immunocompetent hosts by clonal evolution. Attention could be directed to activate the resident immune effectors to break the anergy or tolerance.
Subcutaneous urine injections was practiced in 1912 by Duncan(65) from New York under the name of auto-pyotherapy for urinary infections, and in 1919 by Wildbolz(65) from Bern for diagnostic purposes. Cimino(66) from Palermo reported in 1927 on the use of auto uro-therapy for urinary infections. Rabinowitch(67) in 1931 described this auto-urine therapy for gonarthritis. Jausion et al.(68) used this kind of therapy in 1933 for desensitization and endocrinological problems. They treated with auto urotherapy injections patients who suffered from migraine, pruritus, asthma, urticaria, eczema, psoriasis, etc. Day(69) in 1936 treated patients with acute and subacute glomerulonephritis by injection of an autogenous urinary extract. Sandweiss, Saltzstein and Farbman(70) reported in 1938 that an extract from urine of pregnant women has a prophylactic and therapeutic effect on experimental ulcers in dogs. Shortly thereafter the same group noted that an extract from urine of normal women has a similar beneficial effect(71).
In 1926 Seiffert first described the construction of ileal loop conduits for urinary diversion(72). Bricker in the 1950s popularized the use of the ileal loop as a means of supravesical urinary diversion following exenteration for pelvic malignancy in adults(73). Ureterosigmoidostomy as a means of urinary diversion was used widely from 1920 to 1955. It was this type of implant which Hammer first reported in 1929 associated with tumor(74).
Peyer`s patches are immunocompetent lymphoid organs which participate in intestinal immune responses(75). Epithelial cells within the crypts of the small bowel are one of the fastest dividing cells in the body and yet they show one of the lowest rate of malignant transformation(76). Stem cells in the mucosa of the small bowel can divide every 8 to 12 hours(77). Tapper and Folkman(78) demonstrated that exposure of intestinal segments to urine causes marked lymphoid depletion in the segments. These studies give additional support to the idea that a lymphocyte suppressive factor exist in urine(79). The continued presence of urine bathing the intestinal mucosa appears to locally inhibit regeneration of the Peyer`s patches.
Starkey et al.(80) detected in human urine a material that is biologically and immunologically similar to epidermal growth factor that causes proliferation and keratinization of epidermal tissues.
The increased susceptibility of the colon to cancer associated with the existence of an implanted ureter has been theorized to relate to 3 factore: 1. The role of the urine in the colon(81,82). 2. The mechanical effect of the fecal stream on the stoma(83). 3. The age of the anastomosis(84). Adenocarcinoma of the colon mucosa is a recognized complication of ureterosigmoidostomy. The tumor, which develops adjacent to the junction of the ureter with the bowel, occurs 500 times as often as in the population at large and, in children so operated, 7,000 times as often as in all persons under age 25. The latency period is 5 to 50 years(81,85-87).
It is common knowledge that malignant tumors may disappear spontaneously although very infrequently(88,90).
Usually it is accepted that this could be due at least partly to an immunological reaction(91,92). Renal adenocarcinoma is one of the cancer types in which such spontaneous regressions have been described most frequently(88,90).
Urinary extracts from patients with aplastic anemia(93) and idiopathic thrombocytopenic purpura(94) are capable of stimulating megakaryocyte colony growth in culture, and when injected into rats could also induce thrombocytosis in peripheral blood and megakaryocytosis in the spleens of these animals. Stanley et al.(95) demonstrated that rabbits immunized with human urine concentrates from leukemic patients developed antibody which neutralized the mouse bone marrow colony stimulating factor in human urine and human serum.
Henry Sigerist said, more than 50 years ago: "I personally have the feeling that the problem of cancer is not merely a biological and laboratory problem, but it belongs to a certain extent to the realm of philosophy... All experiments require certain philosophical preparation. And I have the feeling that in the case of cancer many experiments were undertaken without the necessary philosophical background, and therefore proved useless"(96).
Urotherapy is suggested as a new kind of immunotherapy for cancer patients. Unlike the clonal immunotherapy the urine of the cancer patients contain the many tumor antigens which constitute the tumor. Oral auto-urotherapy will provide the intestinal lymphatic system the tumor antigens against which they may produce antibodies due to non-self recognition. These antibodies may be transpierced through the blood stream and attack the tumor and its cells.
1. Root-Bernstein RS. Causality, complementarily, evolution, and emergent properties. In Iversen OH (ed.): New Frontiers in Cancer Causation. Taylor & Francis 1993, p.1-14
2. Burnet FM. The concept of immunological surveillance. Prog Exp Tumor Res 1970;13:1-27
3. Hellstrom I, Hellstrom KE, Zeidman L, Bernstein ID, Brown JP. Cell-mediated reactivity to antigens shared by Moloney virus induced lymphoma cells (LSTRA) and cells from certain
3-methylcholanthrene induced mouse sarcomas. Int J Cancer 1979;23:555-64
4. Hellstrom I, Hellstrom KE, Shepard TH. Cell-mediated immunity against antigens common to tumor colonic carcinomas and fetal gut epithelium. Int J Cancer 1970;6:346-51
5. Hellstrom KE, Hellstrom I. Immunological approach to tumor therapy: Monoclonal antibodies, tumor vaccines, and anti-idiotypes. In Covalently Modified Antigens and Antibodies in Diagnosis and Therapy. Vol.2. Edited by Quash GA, Rodwell JD. Marcel Dekker, Inc., New York 1989, p.1
6. Ehrlich P. In Himmelweit S., ed. The Collected Papers of Paul Ehrlich (translated by P. Alexander). Pergamon Press, Oxford, 1957
7. Watanabe T, Punkel CS, Takeyama H, Lloyd KO, Shiku H, Li LTC, Travassos LR, Oettgen HF, Old LJ. Human melanoma antigen AH is an autologous ganglioside related to GD2. J Exp Med 1982;156:1884-9
8. Rote NS, Gupta RK, Morton DL. Tumor-associated antigens detected by autologous sera in urine of patients with solid neoplasms. J Surg Res 1980;29:18-22
9. Gupta RK, Huth JF, Korn EL, Morton DL. Prognostic significance of urinary antigen analysis by enzyme-linked immunosorbant assay in melanoma patients. Diag Immunol 1983;1:303-309
10. DeVere White RW, Meyers FJ, Soares SE, Miller OG, Soriano TF. Urinary prostate specific antigen levels: Role in monitoring the response of prostate cancer to therapy. J Urol 1992;147:947-951
11. Huland E, Huland H, Meier T, Baricordi O, Fradet Y, Grossman HB, Hodges GM, Messing EM, Schmitz-Draeger BJ. Comparison of 15 monoclonal antibodies against tumor-associated antigens of transitional cell carcinoma of the human bladder. J Urol 1991;146:1631-6
12. Farinati F, Cardin F, Costa F, Nitti D, Di Mario F, Naccarato R. Gastric juice CEA levels: importance of age and gastric mucosal damage. Europ J Cancer Clin Oncol 1986;22:527-9
13. Touitou Y, Proust J, Klinger E, Nakache JP, Huard D, Sachet A. Cumulative effects of age and pathology on plasma carcinoembryonic antigen in an unselected elderly population. Europ J Cancer Clin Oncol 1984;20:369-374
14. Lindholm L, Holmgren J, Svennerholm L, Fredman P, Nillson O, Persson P, Myrvold H, Lagergard T. Monoclonal antibodies against gastro-intestinal tumor-associated antigens isolated as monosialogangliosides. Int Arch Allergy appl Immun 1983;71:178-181
15. Mansson JE, Fredman P, Nilsson O, Lindholm L, Holmgren J, Svennerholm C. Chemical structure of carcinoma ganglioside antigens defined by monoclonal antibody CA50 and some allied gangliosides of human pancreatic adenocarcinoma. Biochim Biophys Acta 1985;834:110-117
16. Holmgren J, Lindholm L, Persson B, Lagergard T, Nilsson O, Svennerholm L, Rudenstam CM, Unsgaard B, Yngvason F, Pettersson S, Killander AF. Detection by monoclonal antibody of carbohydrate antigen CA50 in serum of patients with carcinoma. Brit Med J 1984;288:1479-1482
17. Dienst C, Clodius T, Oldorp T, Uhlenbruch G, Diehl V. CA 19-9, CA50 und CEA bei Pankreas und gastrointestinal Tumoren. Medizin Klin 1987;82:45-50
18. Bruhn HD, Broers H, Euler H, Everding A, Feller AC, Hedderich J, Jostarndt L, Joob B, Zurborn KH, Loffler H. CA 50 im serum von Karzinom-Patienten. Deutsch Med Wochensch 1986;34:1267-1272
19. Farinati F, Holmgren J, Di Mario F, Cardin F, Valliante F, Fanton MC, Della Libera G, Nitti D, Plebani M, Crestani B, Naccarato R. CA 50 determination in body fluids: Can we screen patients at risk for gastric cancer? Int J Cancer 1991;47:7-11
20. Hoffmann JC, Dengler TJ, Knolle PA, Albert-Wolf M, Roux M, Wallich R, Meuer SC. A soluble form of the adhesion receptor CD58 (LFA-3) is present in human body fluids. Eur J Immunol 1993;23:3003-3010
21. Tobi M, Darmon E, Rozen P, Harpaz N, Fink A, Maliakkal B, Halline A, Mobarhan S, Bentwich Z. Urinary organ specific neoantigen. A potentially diagnostic test for colorectal cancer. Dig Dis Sci 1995;40:1531-7
22. Boutwell RK. Evidence that an elevated level of ornithine decarboxylase activity is an essential component of tumor promotion. Adv Polyamine Res 1983;4:127-133
23. lipton A, Sheehan L, Harvey HA. Urinary polyamine levels in patients with gastrointestinal malignancy. Cancer 1975;36:2351-4
24. Loser C, Folsch UR, Paprotny C, Creutzfeldt W. Polyamines in colorectal cancer. Evaluation of polyamine concentrations in the colon tissue, serum and urine of 50 patients with colorectal cancer. Cancer 1990;65:958-966
25. Matsumura Y, Tarin D. Significance of CD44 gene products for cancer diagnosis and disease evaluation. Lancet 1992;340:1053-8
26. Matsumura Y, Hanbury D, Smith JC, Tarin D. Non-invasive detection of malignancy by identification of unusual CD44 gene activity in exfoliated cancer cells. Br Med J 1994;308:619-624
27. Matsumura Y, Sugiyama M, Matsumura S, Hayle AJ, Robinson P, Smith JC, Tarin D. Unusual retention of introns in CD44 gene transcripts in bladder cancer provides new diagnostic and clinical oncological opportunities. J Pathol 1995;177:11-20
28. Zbar B, Tanaka T. Immunotherapy of cancer: regression of tumors after intralesional injection of living Mycobacterium bovis. Science 1971;172:271-273
29. Rosenberg SA, Packard BS, Aebersold PM et al. Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report. N Engl J Med 1988;319:1676-80
30. Hellstrom KE, Hellstrom I. Cellular immunity against tumor specific antigens. Adv Cancer Res 1969;12:167-223
31. Penn I. Tumors of the immunocompromised patient. Ann Rev Med 1988;39:63-73
32. Vanky F, Klein E, Willems J et al. Lysis of autologous tumor cells by blood lymphocytes activated in autologous mixed lymphocyte tumor cell culture - no correlation with the postsurgical clinical course. Cancer Immunol Immunother 1987;24:180
33. Vanky F, Klein E. Specificity of auto-tumor cytotoxicity exerted by fresh, activated and propagated human T lymphocytes. Int J Cancer 1982;29:547
34. Knuth A, Wolfel T, Klehmann E, Boon T, Meyer zum Buschenfelde KH. Cytolytic T cell clones against an autologous human melanoma: Specificity study and definition of three antigens by immunoselection. Proc Natl Acad Sci (USA) 1989;86:2804-8
35. LoBuglio AF, Neidhart JA. A review of transfer factor immunotherapy in cancer. Cancer 1974;34:1563-70
36. Levin AS, Byers VS, Fudenberg HH, Wybran J, Hackett AJ, Johnston JO, Spitler LE. Osteogenic sarcoma. Immunologic parameters before and during immunotherapy with tumor-specific transfer factor. J Clin Invest 1975;55:487-99
37. Rosenberg SA, Schearz SL, Speiss PJ. Combination immunotherapy for cancer: synergistic antitumor interactions of interleukin-2, alpha interferon and tumor-infiltrating lymphocytes. JNCI 1988;80:1393-1397
38. Rosenberg SA, Aebersold P, Cornetta K et al. Gene transfer into humans: immunotherapy of melanoma using tumor-infiltrating lymphocytes modified by retroviral gene transduction. N Engl J Med 1990;323:570-578
39. Russell SJ, Eccles SA, Fleming CL, Johnson CA, Collins MKL. Decreased tumorigenicity of a transplantable rat sarcoma following transfer and expression of an IL-2 cDNA. Int J Cancer 1991;47:244-252
40. Hellstrom KE, Hellstrom I, Kant JA, Tamerius JD. Regression and inhibition of sarcoma growth by interference with a radiosensitive T cell population. J Exp Med 1978;148:799-804
41. Estin CD, Stevenson US, Hellstrom I, Hellstrom KE. Cyclophosphamide potentiates the antitumor activity of v-p97NY. Cell Immunol 1989;120:126-31
42. Nepom GT, Hellstrom KE. Anti-idiotypic antibodies and the induction of specific tumor immunity. Cancer Metast Rev 1987;6:489-502
43. Schwartz RH. A cell culture model for T lymphocyte clonal anergy. Science 1990;248:1349-1356
44. Jenkins MK, Schwartz RH. Antigen presentation by chemically modified splenocytes induces antigen-specific T cell unresponsiveness in vitro and in vivo. J Exp Med 1987;165:302-319
45. Mowat AM. The regulation of immune responses to dietary protein antigens. Immunol Today 1987;8:93-98
46. Weiner HL, Zhang ZJ, Khoury SJ, Miller A, Al-Sabbagh A, Brod SA, Lider O, Higgins P, Sobel R, Nussenblatt RB, Hafler DA. Antigen-driven peripheral immune tolerance. Suppression of organ-specific autoimmune diseases by oral administration of autoantigens. Ann NY Acad Sci 1991;636:227-232
47. Sercarz E, Krzych U. The distinctive specificity of antigen-specific suppressor T cells. Immunol Today 1991;12:111-118
48. Green DR, Flood PM, Gershon RK. Immunoregulatory T-cell pathways. Annu Rev Immunol 1983;1:439-463
49. Thurau SR, Caspi RR, Chan CC, Weiner HL, Nussenblatt RB. Immunological suppression of experimental autoimmune uveitis. Fortschr Ophthalmol 1991;88:404-407
50. Nussenblatt RB, Caspi RR, Mahdi R, Chan CC, Roberge F, Lider O, Weiner HL. Inhibition of S-antigen induced experimental autoimmune uveoretinitis by oral induction of tolerance with S-antigen. J immunol 1990;144:1689-1695
51. Brandtzaeg P. Overview of the mucosal immune system. Curr top Microbiol Immunol 1989;146:13-28
52. MesteckyJ, McGhee JR. Oral immunization: Past and present. Curr Top Microbiol Immunol 1989;146:3-12
53. Stokes CR. Induction and control of intestinal immune responses. In Newby TJ, Stokes CR (eds.): Local immune responses of the gut. Boca Raton, CRC Press, 1984,pp.97-142
54. Hanson DG, Vaz NM, Rawlings LA, Lynch JM. Inhibition of specific immune responses by feeding protein antigens. II. Effects of prior passive and active immunization. J Immunol 1979;122:2261-2266
55. Brandtzaeg P, Baklien K, Bjerke K, Rognum TO, Scott H, Valnes K. Nature and properties of the human gastrointestinal immune system. In Miller K, Nicklin S (eds.):Immunology of the Gastrointestinal Tract. Boca Raton, CRC Press, 1987, pp.1-88
56. Peng HJ, Turner MW, Strobel S. The generation of a "tolerogen" after the ingestion of ovalbumin is time-dependent and unrelated to serum levels of immunoreactive antigen.Clin Exp Immunol 1990;81:510-515
57. Stokes CR, Swarbrick ET, Soothill JF. Genetic differences in immune exclusion and partial tolerance to ingested antigens. Clin Exp Immunol 1983;52:678-684
58. Swarbrick ET, Stokes CR, Soothill JF. Absorption of antigens after oral immunization and the simultaneous induction of specific systemic tolerance. Gut 1979;20:121-125
59. Miller A, Zhang AJ, Prabdu-Das M, Sobel A, Weiner HL. Active suppression vs. clonal anergy following oral or IV administration of MBP in actively and passively induced EAE. Neurology 1992;42(Suppl 3):301
60. Lamont AG, Gordon M, Ferguson A. Oral tolerance in protein deprived mice. II. Evidence of normal 'gut processing' of ovalbumin, but suppressor cell deficiency, in deprived mice. Immunology 1987;61:339-343
61. Hanson DG, Vaz NM, Maia LC, Hornbrook MM, Lynch JM, Roy CA. Inhibition of specific immune responses by feeding protein antigens. Int Arch Allergy Appl Immunol 1977;55:526-532
62. Matthews JB, Fivaz BH, Sewell HF. Serum and salivary antibody responses and the development of oral tolerance after oral and intragastric antigen administration. Int Arch Allergy Appl Immunol 1981;65:107-113
63. Higgins P, Weiner HL. Suppression of experimental autoimmune encephalomyelitis by oral administration of myelin basic protein and its fragments. J Immunol 1988;140:440-445
64. Miller A, Lider O, Al-Sabbagh A, Weiner HL. Suppression of experimental autoimmune encephalomyelitis by oral administration of myelin basic protein. J Neuroimmunol 1992;39:243-250
65. Jausion H. Sur l'auto-ouro-therapie. Journal D'Urologie 1935;39:58-59
66. Cimino T. Premiers essais de vaccine-proteine-therapie des infections non gonococciques ni tuberculeuses des voies urinaires a l'aide des injections sous-cutanees de l'urine purulente du sujet, sterilisee par l'ebullition (ouro-therapie). Rivista Sanitaria 1927;186
67. Rabinowitch IM. Auto-urine-therapy in gonarthritis. Vratchebnaia gazeta 1931;35:677-8
68. Jausion H, Giard R, Martinaud G. L'auto-ouro-therapie. La Presse Medicale 1933;76:1467-1470
69. Day HB. Treatment of glomerulonephritis by antigen. Lancet 1936;1456-9
70. Sandweiss DJ, Saltzstein HC, Farbman AA. The prevention or healing of experimental ulcer in Mann-Williamson dogs with the Anterior-Pituitary-Like hormone (Antuitrin-S). Am J Dig Dis 1938;5:24-30
71. Sandweiss DJ, Saltzstein HC, Farbman AA. The relation of sex hormones to peptic ulcer. Am J Dig Dis 1939;6:6-12
72. Seiffert L. Die "Darn-Siphonblase". Arch fur Klin Chir 1935;183:569
73. Bricker EM. Bladder substitution after pelvic evisceration. Surg Clin North Am 1950;30:1511
74. Hammer E. Cancer du colon sigmoide dix ans après implantation des ureteres d'une vessie exstrophiee. J Urol Nephrol 1929;28:260
75. Miller-Schoop JW, Good RA. Functional studies of Peyer`s patches: Evidence for their participation in intestinal immune responses. J Immunol 1975;144:1757
76. Barclay THC, Schapira DV. Malignant tumors of the small bowel. Cancer 1983;51:878-881
77. Loeffler M, Stein R, Wichmann HE, Potten CS, Kaur P, Chwalinski S. Intestinal cell proliferation. I. A comprehensive model of steady-state proliferation in the crypt. Cell Tissue Kinet 1986;19:627-645
78. Tapper D, Folkman J. Lymphoid depletion in ileal loops: Mechanism and clinical implications. J Pediatr Surg 1976;11:871-880
79. Wilson WEC, Kirkpatrick CH, Talmage DW. Suppression of immunologic responsiveness in uremia. Ann Intern Med 1965;62:1
80. Starkey RH, Cohen S, Orth DN. Epidural growth factor: Identification of a new hormone in human urine. Science 1975;189:800-802
81. Urdaneta LF, Duffell D, Creevy CD, Aust JB. Late development of primary carcinoma of the colon following ureterosigmoidostomy: report of three cases and literature review. Ann Surg 1966;164:503-13
82. Harguindey SS, Colbeck RC, Bransome ED JR. Ureterosigmoidostomy and cancer: new observations (letter). Ann Intern Med 1975;83:833
83. Rivard JY, Bedard A, Dionne L. Colonic neoplasms following ureterosigmoidostomy. J Urol 1975;113:781-6
84. Carswell JJ III, Skeel DA, Witherington R, Otken LB Jr. Neoplasia at the site of ureterosigmoidostomy. J Urol 1976;115:750-2
85. Lasser A, Acosta AE. Colonic neoplasms complicating ureterosigmoidostomy. Cancer 1975;35:1218-22
86. Sooriyaarachchi GS, Johnson RO, Carbone PP. Neoplasms of the large bowel following ureterosigmoidostomy. Arch Surg 1977;112:1174-7
87. Eraklis AJ, Folkman MJ. Adenocarcinoma at the site of ureterosigmoidostomies for exstrophy of the bladder. J Pediatr Surg 1978;13:730-4
88. Everson T. Spontaneous regression of cancer. Ann NY Acad Sci 1964;114:721-35
89. Stephenson H, Delmez J, Renden D, Kimpton R, Todd P, Charron T, Lindberg D. Host immunity and spontaneous regression of cancer evaluated by computerized data reduction study. Surg Gynecol Obstet 1971;133:649-55
90. Cole W. Spontaneous regression of cancer: The metabolic triumph of the host? Ann NY Acad Sci 1974;230:111-41
91. Burnet F. Immunological aspects of malignant disease. Lancet 1967;II:1171-4
92. Droller M. Immunotherapy and genitourinary neoplasia. Urol Clin N Am 1980;7:831-46
93. Enomoto K, Kawakita M, Kishimoto S, Katayama N, Miyake T. Thrombopoiesis and megakaryocyte colony stimulating factor in the urine of patients with aplastic anemia. Br J Haematol 1980;45:551-556
94. Kawakita M, Enomoto K, Katayama N, Kishimoto S, Miyake T. Thrombopoiesis and megakaryocyte colony stimulating factors in the urine of patients with idiopathic thrombocytopenic purpura. Br J Haematol 1981;48:609-615
95. Stanley ER, McNeill TA, Chan SH. Antibody production to the factor in human urine stimulating colony formation in vitro by bone marrow cells. Br J Haematol 1970;18:585-590
96. Galdston I. The ideological basis of discovery. Bull Hist Med 1939;7:729-735