Spleen – Structure and Function
The spleen is located in the left hypochondriac region of the abdomen between the fundus of the stomach and diaphragm. In adults, it is approximately 12 cm long, 7 cm wide, and 3 cm in thickness, and weighs around 150-250 g. The splenic artery, splenic vein, efferent lymphatic vessels and splenic nerve plexus pass through the hilus, which is a depressed area in the capsule.1, 2, 3
The spleen is the largest organ of the lymphatic system and contributes to a fully operational immune system as it combines the innate and adaptive immune system in a uniquely organized way. The structure of the spleen enables it to remove older red blood cells from circulation and leads to the efficient removal of blood-borne microorganisms and cellular debris. This function, in combination with a highly organized lymphoid compartment, makes the spleen the most important organ for antibacterial and antifungal immune reactivity.
The spleen is an organ which not only effectively uses its own immune cells but also mobilizes the body’s immune cells for immune surveillance and for the protection of other vital organs including the heart, kidney and brain.4, 5, 6, 7 The spleen is prone to physical injury, infections, and various immunological conditions including cancers. Enlargement of the spleen or splenomegaly may occur due to anemia, infections, inflammation, cancer, metabolic disorders, and liver diseases.
The spleen has four important structures:
and marginal zone.
Each area shows unique morphological structure and is involved in performing specific physiological functions. The capsule contains dense connective tissues, elastic and smooth muscle fibers, and sympathetic nerve fibers from the splenic nerve plexus. The cells which play an important role in spleen functions are macrophages, monocytes, natural killer (NK) cells, and B- and T-cells.
Red pulp constitutes about 70% of the total splenic volume in adults and contains numerous sinuses which are filled with blood, rich in platelets. Between the sinuses are spongy cellular cords (cords of Billroth), made up of reticular fibers and reticular cells intermingled with several immune cells, such as macrophages, monocytes, granulocytes, B-cells, T-cells and plasma cells. In the red pulp, pathogens and cellular debris, as well as aging erythrocytes, are efficiently removed from the blood by macrophages, which are abundant in this compartment. These macrophages are then well equipped to recycle iron from the erythrocytes. Several red pulp specific functions occur in the spleen including blood filtration, antigenic stimulation and proliferation of B- and T-cells and production of antibodies of different specifications.
The Marginal Zone
The marginal zone forms a bridge between the innate and adaptive immune response, because the macrophages in this region, which express specific pattern-recognition receptors, can efficiently take up blood-borne pathogens. The specific subset of B-cells in this region, the marginal-zone B-cells, can be activated by these macrophages or can directly respond to blood-borne pathogens, after which they become antigen-presenting cells or IgM-producing plasma cells. Entry of activated dendritic cells or marginal-zone B-cells to the white pulp can initiate an adaptive immune response through activation of T-cells, which then migrate to the edge of the B-cell follicles and provide help to B-cells.
Immunological activation of B-cells occurs in the marginal zone as a result of antigenic encounter.8 Many lymphocytes in the marginal zone migrate into respective T- and B areas. The marginal zone contains the highest concentration of blood antigens of any other area in the spleen because splenic arterial blood empties into the marginal zone. Marginal zone B-cells show somatic hypermutation, clonal expansion and B-cell positive selection.9, 10 B-cell clonal expansion also occurs in the germinal center of the B-cell follicle following antigenic stimulation.
The white pulp is a lymphocyte rich area which contains periarterial lymphatic sheath (PALS) around the arterial vessels - particularly around the central artery and central arterioles, follicles and loose lymphatic tissues. The PALS is a sheath of lymphocytes mostly CD4+ T-cells that envelope the central arterial vessels. The follicles not only contain B-cells, but also T-cells, which are found adjacent to the PALS. Significant immunological activities and cell trafficking and cross-talk between various immune cells occur. Bordering the PALS and the follicles is the marginal zone, which has few lymphocytes but numerous macrophages and antigen presenting cells (APCs).
The white pulp is a highly organized lymphoid region where adaptive immune responses can be initiated. It is composed of separate areas for B-cells and T-cells, which are surrounded by the marginal zone - a region that contains discrete subsets of macrophages and B-cells. Whereas blood flows freely through the marginal zone, the white pulp is excluded from the bloodstream, and specific signals are required for entry.
Entry of leukocytes to the white pulp requires activation of G-protein-coupled receptors, a process which is reminiscent of the multistep extravasation process that has been described for leukocytes leaving the bloodstream and entering the lymph nodes or sites of inflammation.
The organization of the white pulp into distinct areas, which promotes efficient interaction of immune system cells, is coordinated by the expression of chemokines, which attract the specific lymphoid subsets to the appropriate microdomains. In addition, the organization of both the white pulp and the marginal zone is under strict control of lipid mediators and adhesion molecules, as well as chemokines, all of which help the specific cellular subsets be retained within their compartments. Expression of these factors is, in turn, controlled by activation of the lymphotoxin-β receptor and tumor-necrosis-factor receptor-1, but it might also involve additional signaling receptors. Through this unique organization of its compartments, the spleen can mount complex adaptive immune responses, as well as effectively clear pathogens from the blood.
For more than 50 years, splenic peptides have been used as an immunological supportive tumor therapy aimed at improving patients’ poor general state of health. Splenic peptides are obtained from porcine spleen. The main constituents of the active ingredients in splenic peptides are oligopeptides and polypeptides. However, depending on the method of manufacture, splenic peptide preparations may vary widely in their individual composition.
Spleen peptide preparations are primarily used in cancer therapy and immunotherapy in Europe and have a multitude of effects on the body. They can improve the supply of oxygen to the cells, for example, by up to 200%. As a result, an increase in the strength of the defenses can be expected and the lymphatic system also receives considerable stimulation. This, in turn, is important for detoxification of the body, e.g. particularly when fighting cancer cells. Spleen peptides also activate and stabilize numerous psycho-neuroendocrine regulatory mechanisms. They show molecular similarities to neuropeptides and, like them, act on a wide variety of metabolic areas via hormones and cell messengers. This harmonizes and regulates the psycho-neuroendocrine and defense-regulating functions.
Spleen peptides can be used in a variety of conditions but are most notable for improving both immunity and cellular detoxification. They are indicated in defective or decreasing function of psycho-neuroendocrine immunological regulation, but particularly in degenerative diseases, menopausal symptoms, and allergy. Research, as well as practical therapeutic experience, also shows that the regular use of spleen peptides improves the regulatory action on body functions in numerous disorders. Another concomitant effect of spleen peptide therapy is that it is often possible to eliminate or considerably reduce dosages of other pharmaceuticals that cause side effects.
Certain splenic peptides have been shown to bind to specific receptors on the surface of white cells such as macrophages and polymorphonuclear leukocytes. This, in turn, stimulates their migration, phagocytic, bactericidal, and tumoricidal (antitumor) activity.11 Splenic peptides can restore immune functions damaged by radiation and chemotherapy. They stabilize the lymphocytic status and improve the patient’s general health.12
Commercial Spleen Peptide Preparations
Peptides are short chains of amino acid monomers linked by peptide (amide) bonds. Peptides are chemical messengers that are universal regulators and stabilizers of cell functions throughout the body. Peptides control cell growth, stabilize critical cell functions, and provide essential means for cells to communicate with each other. Peptides possess the unique action of serving to convey information from one cell to another. Without proper communication and coordination among all cells, molecules and organs of the immune system “network”, it cannot function properly.
Spleen peptides serve to regulate and stabilize the cells of the immune system. Several splenic peptide preparations are available in Europe for enhancing immune function, particularly after surgery, radiation therapy, and cytotoxic chemotherapy.
Most conventional U.S. oncologists will know little - if anything - about this type of peptide therapy. With no knowledge, most physicians will not recommend trying it, even though side effects are almost non-existent. Additionally, medical websites such as pharmaceutically oriented WebMD discourage patients from using spleen peptides and falsely claim that there is insufficient evidence for their use. In truth, research of injectable spleen peptide efficacy for numerous conditions has been both positive and extensive.13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33
One of the most researched spleen peptide preparations is Polyerga®. German drug regulatory authorities have approved this product for use in that country. Polyerga® is available in both oral form, as well as injectable, and is manufactured by HorFerVit Pharma GmbH. The oral form of Polyerga® is available as polypeptide tablets or oligopeptide capsules. 1 Dragee contains: oligo- and polypeptides from porcine spleen 100 mg. Recommended dosage according to the manufacturer is one tablet to be taken before meals, three times daily. An additional capsule may be taken every other day before a meal.
The injectable form of Polyerga® comes in 1 ml “Ampullen” (vial) and contains: oligopeptides from porcine spleen 30 μg.; phenol 0.05% as stabilizer, sodium chloride, sodium hydroxide, and water. Dosage is according to the individual and condition being treated. According to the manufacturer, a typical dosage is as follows: for one week from Monday - Friday administer 1 vial daily. Then for two weeks, three times a week, administer 1 vial. After that, administer 1 vial twice a week for three weeks.
Treatment recommendations by the German Society for Thymus Therapy
The German Society for Thymus Therapy has a slightly different schedule for injectable spleen peptides (see below).34 They recommend that spleen peptides should be administered as long-term therapy. Only in this way can the desired effects be achieved and maintained over a long period.
M = injection of 5 ml spleen peptides, total of 20 spleen peptide injections in 6 weeks, followed by transition to 1 injection per week every 14 days or once a month, depending on the status of the illness. After an intensive initial course of 20 injections over 6 weeks, booster intervals are fixed depending on the patient’s condition. Booster injections every 2 weeks have proved successful in chronic and geriatric conditions. The basic regime can be intensified in severe illness or extended for general preventive purposes.
Further administration of spleen peptides is determined on an individual case basis by the physician and depends on the patient's condition and tolerance of therapy. Repeated treatment is recommended after 6 weeks or 3 months. In severe cases, long-term therapy where 1 vial of Polyerga® is administered 1-2 times a week may be considered.
The combination of thymic peptides and splenic peptides is useful in general immune deficiencies and reduced resistance during cancer treatment. While thymic peptides regulate T-lymphocytes and recruit new T-cells from the bone marrow, splenic peptides have a greater influence on the B-lymphocytic defenses. Hence, patients whose immune systems are suppressed due to radiation and cytotoxic chemotherapy are good candidates for spleen peptide therapy. These treatments can be used together or separately and, like all treatment plans, should be individualized to the patient’s condition.
Combination with other forms of treatment
The combination of thymic peptides (thymosin) and spleen peptides is useful in general immune deficiencies and reduced resistance. While thymic peptides regulate T-lymphocytes and recruit new T-cells from the bone marrow, spleen peptides have a greater influence on the B-lymphocytic defenses. These limit the overproduction of immunoglobulins. The German Society for Thymus Therapy recommends the following 10-week schedule for combined thymic peptides and spleen peptides.
M = injection of 5 ml spleen peptides; T = Thymus peptides
There are no restrictions regarding other treatment methods. Additional measures may include: dietary changes, supplementation with antioxidants - A, C, E, proteolytic enzymes, minerals - magnesium, potassium, zinc, selenium, neural therapy, etc.
Gynecological and androgenic tumors should not be treated with injectable spleen peptides until further research is performed. In pregnant women, caution is appropriate, as spleen peptides act on the hormonal system. In some diseases, the dosage of other drugs can be reduced during the course of spleen therapy. In diabetics, blood sugar levels should be monitored to recognize possible reductions of insulin etc. in good time. The same applies to patients with a tendency to overactive thyroid or goiter. Doses of thyroid hormones may possibly need to be reduced. Patients receiving cortisone or non-steroidal anti-inflammatory drugs can often be placed on lower doses. For patients being treated for gout, uric acid values should be monitored.
As with all medicines, hypersensitivity reactions can occur in predisposed individuals. They are almost never seen in patients receiving intramuscular injection of spleen peptides. However, to rule out the possibility of such a situation, a preliminary test should be performed with 0.1 ml spleen peptides before starting the course of injections.
Gray’s Anatomy: The Anatomical Basis of Clinical Practice. Editor- in - Chief S. Standring, 2008. Churchill Livingstone, Elsevier, pp.1192-5.
Fawcett, D.W. & Jensh R.P. (2002). Bloom & Fawcett’s Concise Histology, 2nd edition, Arnold, New York. pp. 159- 61.
Guyton A.C. and Hall J.E. (2006). Text book of Medical Physiology. Elsevier Saunders. pp. 180, 440.
R.E.Mebius and G.Kraal. Structure and function of the spleen. Nat. Rev. Immunol. 5(8),(2005), 606-16.
J.M. den Haan and G. Kraal. Innate immune functions of macrophage subpopulations in the spleen. J. of Innate Immunity 4(5-6), (2012), 437- 445.
X. Zhao, N. Wu, and L. Huang. Endothelial progenitor cells and spleen: New insights in regeneration medicine. Cytotherapy, 12(1), (2010), 7-16.
S.M. Hamza, and S. Kaufman. Role of spleen in integrated control of splanchnic vascular tone: physiology and pathophysiology. Can J Physiol. and Pharmacol. 87(1), (2009), 1-7.
A. Cerutti. M.Cols, and I. Puga. Marginal zone B cells: virtues of innate like antibodyproducing lymphocytes. Nat. Rev. Immunol. 13 (2), (2013), 118-132.
A. Tierens, J. Delabie, L. Michiels et al. Marginal zone B cells in the human lymph node and spleen show somatic hypermutations and display clonal expansion. Blood 93(1), (1999), 226- 234.
L. Wen, J. Brill-Dashoff, S.A. Shinton, M. Asano, R.R. Hardy, K. Hayakawa. Evidence of marginal zone B cells-positive selection in spleen. Immunity 23, (2005), 297-3008.
Najjar V, Nishioka K (1970). Tuftsin: a natural phagocytosis stimulating peptide (abstract page). Nature 228 (5272): 672–3.
Jurin M, Zarković N, Ilić Z, Borović S, Hartleb M. Clin Porcine splenic peptides (Polyerga) decrease the number of experimental lung metastases in mice. Exp Metastasis. 1996 Jan; 14(1):55-60.
Zarkovic N, Hartleb M, Zarkovic K, Borovic S, Golubic J, Kalisnik T, Frech S, Klingmüller M, Loncaric I, Bosnjak B, Jurin M, Kuhlmey J. Spleen peptides (Polyerga) inhibit development of artificial lung metastases of murine mammary carcinoma and increase efficiency of chemotherapy in mice. Cancer Biotherapy and Radiopharmaceuticals 03/1998; 13(1):25-32.
Gulubova MV, Ganeva MG, Zaneva MA. Rat liver pit cells following administration of the glycopeptide preparation (Polyerga). Hepatogastroenterology. 1995 Sep-Oct;42(5):698-704.
Borghardt, Jürgen, Bernd Rosien, Roman Görtelmeyer, Svenja Lindemann, Martin Hartleb, and Martin Klingmüller. Effects of a spleen peptide preparation as supportive therapy in inoperable head and neck cancer patients. Arzneimittelforschung 50, no. 02 (2000): 178-184.
Aina, Olulanu H., Thomas C. Sroka, Man‐Ling Chen, and Kit S. Lam. Therapeutic cancer targeting peptides. Peptide Science: Original Research on Biomolecules 66, no. 3 (2002): 184-199.
van’t Veen, A., H. De Ruyter, J. W. Mouton, M. Hartleb, and B. Lachmann. Pretreatment with spleen peptides can enhance survival in influenza A infected mice. Complementary Medicine Research 3, no. 5 (1996): 218-221.
Jayatilake, R. S., J. Balawardena, G. Skiba, and M. Hartleb. Spleen peptides enhance body weight, subjective well-being and appetite in cancer patients. J Cancer Res Clin Oncol 118 (1992): R36.
Hartleb, M., and J. Leuschner. Toxicological profile of a low molecular weight spleen peptide formulation used in supportive cancer therapy. Arzneimittel-Forschung 47, no. 9 (1997): 1047-1051.
De Ojeda, G., R. Diez-Orejas, P. Portoles, M. Ronda, M. L. Del Pozo, M. J. Feito, M. Hartleb, and J. M. Rojo. Polyerga, a biological response modifier enhancing T-lymphocyte-dependent responses. Research in Experimental Medicine 194, no. 1 (1994): 261-267.
Vassilev, M., E. Zacharieva, K. Antonov, and T. Krastev. Treatment of chronic hepatitis B patients with Polyerga™. Journal of Hepatology 23, no. supplement 1 (1995): 197.
Chiarotto, J., M. Tthirlwell, M. Trudeau, J. Skelton, G. Boos, and J. Viallet. Phase-I-II Trial of an Unconventional Agent, Polyerga, in Patients with Advanced Cancer. In Clinical Research, vol. 42, no. 1, pp. A104-A104. 6900 Grove Rd, Thorofare, NJ 08086: Slack Inc, 1994.
Dittrich, W., H. Rothe, P. P. Jaros, and A. Willig. Biological properties and partial purification of a growth factor from porcine spleen. Experimental cell research 188, no. 1 (1990): 172-174.
Dold, Ulrich, and Bundesarbeitsgemeinschaft für Rehabilitation. Krebszusatztherapie beim fortgeschrittenen nicht-kleinzelligen Bronchialkarzinom: multizentrische kontrollierte Studie zur Prüfung der Wirksamkeit von Iscador und Polyerga. Thieme, 1991.
Klose, G., and J. Mertens. Long term results of postoperative treatment of carcioma of the stomach with Polyerga. Therapiewoche 27 (1977): 5359-5361.
Baier, J. E., H. A. Neumann, T. Taufighi-Chirazi, and H. Gallati. Thymopentin, Factor AF2, and Polyerga Improve Impaired Mitogen Induced Interferon-gamma Release of Peripheral Blood Mononuclear Cells Derived from Tumor Patients. Tumordiagnostik und Therapie 15, no. 1 (1994): 21-21.
Berressem, P., S. Frech, and M. Hartleb. Additional Therapy with Polyerga [R] Improve Immune Reactivity and Quality of Life in Breast Cancer Patients during Rehabilitation. Tumordiagnostik und TherapieTUMORDIAGNOSTIK UND THERAPIE 16, no. 2 (1995): 45-45.
Yong, Chen, and Zhang En-Pi. Therapeutic Effect of Radiation Combined with Polyerga in the Treatment of Nasopharyngeal Carcinoma [J]. Chinese Journal of Clinical Oncology 5 (1997): 017.
Dehai, T., and Z. Xianchun. Clinical study on combined treatment of esophageal carcinoma with radiotherapy and polyerga. Chin J Clin Oncol 25 (1998): 468-70.
Liqin, Shen. Immunologic Functional Effect of Polyera in Cancer Patients [J]. Suzhou University Journal of Medical Science 1 (1997): 030.
Mingqian, Xu Xinhua Hu Shan Lu. The Effect of Polyerga in Combined with Repeated Chemotherapy of Recurrent Non Hodgkin’s Lymphoma. Chinese Journal of Clinical OncologyCHINESE JOURNAL OF CLINICAL ONCOLOGY (1998): 06.
ZHAO, Xiao-wu, Xiao-jing PENG, and Yue-wen FU. Laboratory Study and Clinical Application of Polyerga in Purging auto Transplantation [J]. Henan Journal of Oncology 6 (2000): 003.
Guibo, Gao, Li Zhengping, and Li Jianhua. Abstraction of Spleen Peptide and Its Therapeutic Effect in the Treatment of Malignant Tumor [J]. Chinese Journal of Rehabilitation 3 (1999): 014.