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Designed on October, 2008 by Ivan Bubanovic
New book by Ivan Bubanovic
Origin of Anti-tumor Immunity Failure in Mammals
Translated by Marija Rusimovic
Download Contents-Introduction .pdf file
Also available at www.medicalbooks.com, www.amazon.com, www.springeronline.com, etc
"...sciences long ago
recognized that observations are not superior to hypotheses in
generating scientific progress nor are hypotheses superior to
observations. Both are necessary."
David F. Horrobin
(1939-2003)
Origin of anti-tumor immunity
failure in mammals and new possibility for immunotherapy
Ivan Bubanovic
Department of Obstetrics and Gynecology - Health Centre - Gnjilane, Serbia and Montenegro
Medical Hypotheses, 2003;60(2):152-158.
ABSTRACT
There is now much evidence that tumors can be immunogenic. Tumor cells very often express antigens in a form recognizable by the host immune system, but most frequently without consequences on tumor progression. This has been shown in many experimental models and different experimental conditions. Immediate mechanisms for the escape of tumors from immune response are very similar with mechanisms for the escape of fetoplacental unit (as an allograft) from maternal immune response. Similarity between these two mechanisms is so significant that any randomness is banished. Mechanisms of anti-tumor immunity in mammals are substantially different in comparison with mechanisms of anti-tumor immunity in other classes of vertebrates. Moreover, type of most frequently tumors in non-mammalians vertebrates is also significant different. Incidence of malignant tumors in non-mammalians vertebrates is significantly less than incidence of malignant tumors in mammals. These facts indicate that immune system of mammals during anti-tumor immune response is tricked with similarity between tumor cells and trophoblast or other placental cells. It may be a specific evolutionary approach in rendering of anti-tumor immunity failure in mammals, and new possibility for anti-tumor immunotherapy.
Induction of thymic tolerance
as possibility in prevention of recurrent spontaneous abortion
Ivan Bubanovic
Department of Obstetrics and Gynecology - Health Centre in Gnjilane, Serbia and Montenegro
Medical Hypotheses, 2003;60(4):520-524.
ABSTRACT
A major process through which the immune system becomes tolerant to self-proteins involves the deletion of self-reactive cells in the thymus and/or inhibition of specific Th1 cells clones. Deletion process includes two selection mechanisms in which the thymus eliminates unwanted thymocytes are known as positive selection and negative selection. The thymus is an antigenically privileged site, mainly for it is discrete by blood-thymus barrier. Many researches were shown that intrathymic inoculation of any antigen resulted in specific tolerance induction. The embryo/fetus and placenta are an allograft to which the mother must remain immunologically tolerant in order for the fetus to survive. Today, there is much interest focused on the immunology of recurrent spontaneous abortion (RSA). Up to 50% of RSA may be mediated by the immune system via inadequate maternal anti-paternal response. Nature of this maternalâ??fetal disturbance represents disbalance in Th1/Th2 activity. Contra-shift in Th1/Th2 activity is the basis for immunotherapy with paternal leukocyte immunization (PLI). PLI induce some kind of peripheral tolerance on embryonic/fetal/trophoblast antigens, but problems of central tolerance are still open. Intrathymic inoculation of fetal or paternal cells (like leukocyte, thymic dendritic cells, trophoblast cells) or paternal set of MHC molecules may cause central specific tolerance and may be a new possibility for immunotherapy in RSA patients.
Failure of blood-thymus barrier as a
mechanism of tumor and trophoblast escape
Ivan Bubanovic
Department of Obstetrics and Gynecology - Health Centre - Gnjilane, Serbia and Montenegro
Medical Hypotheses, 2003;60(3):315-320.
ABSTRACT
A major process through which the immune system becomes tolerant to self-proteins involves the deletion of self-reactive clones in the thymus, but clonal deletion is not single mechanisms of thymic tolerance. There is now much evidence that intrathymic antigen expression results in anergy induction of T helper type-1 (Th1) clones in the periphery. Bloodâ??thymus barrier is most important structure for prevention of unwanted penetration of antigens into the thymus. Unpermeability of the barrier restrain induction of acquired thymic tolerance on unwanted antigens like microbes and tumor cells. Nevertheless, one of most important mechanism of tumor and trophoblast escape is in anergy of Th1 cells and in Th2 cells domination. Many mechanisms are included in disarrangement of Th1/Th2 balance in pregnancy and tumor bearers, but one of possibility is in failure of bloodâ??thymus barrier. Possible consequences of bloodâ??thymus barrier failure are trophoblast-specific or tumor-specific antigens penetrate into the thymus, deletion or anergy of antigen-specific clones and acquired thymic tolerance induction. Bloodâ??thymus barrier is variable structure in anatomical and functional sense so that in certain condition foreign antigens probably can permeate across the barrier. Probability that some factors like hormones, cytokines, prostaglandine and neuromediators can affect bloodâ??thymus barrier permeability and contribute in mechanisms of trophoblast and tumor escape is real but relatively unexplored.
Crossroads of extrathymic
lymphocytes maturation pathways
Ivan Bubanovic
Department of Obstetrics and Gynecology - Health Centre in Gnjilane, Serbia and Montenegro
Medical Hypotheses, 2003;61(2);235-239.
ABSTRACT
The majority of T cells located in peripheral lymphoid organs are dependents on the thymus for regular differentiation and function. Only a minority of T lymphocytes are thymus-independent. These cells pass by extrathymic maturation processes and become mature T lymphocytes. Some data suggest that mechanism of extrathymic lymphocytes maturation (eTLM) includes migration, proliferation, differentiation and selection of lymphocytes as well as thymic pathway. With aging and progression of thymic involution or in accidental thymic involution, pathway of eTLM derives emphasis. T cells from extrathymic pathway probably can polarize action of thymic-dependent T cells or participate in immune reaction in antigen-destructive or antigen-protective manners. Consequently, extrathymic pathways can be a source of self-reactive T cells or cells which participate in mechanisms of trophoblast or tumor escape. Results of eTLM probably are not presets, already depend upon many factors and microenvironmental snapshots. Factors like cytokines, prostaglandine, microbes, MHC molecules, hormones, Fas ligand, heat shock proteins, phenotypes of dendritic cells and APCs, probably can be polarizing courses of eTLM pathway. Definitive to the course of extrathymic-derived cells action, presumably is resultant of microenvironmental relations and interactions of foregoing factors. Hypothesis that microbes, especially viruses, can be promoters of extrathymic (self)antigen-reactive lymphocytes maturation is real as well as hypothesis that extrathymic lymphocytes selection and products of selected lymphocytes can be included in mechanisms of tumor, trophoblast and transplant rejection or escape.
1a,25-dihydroxy-vitamin-D3 As New Immunotherapy in Treatment of Recurrent Spontaneous Abortion
Ivan Bubanovic
Department of Gynecology and Obstetrics â?? â??Medica Centreâ?? â?? Nis, Serbia and Montenegro
Medical Hypotheses, 2004;63(2):250-253.
ABSTRACT
Recurrent spontaneous abortion (RSA) is important health problem affecting 2-5% of reproducing couples worldwide. It has long been suspected that nearly 80% of the unexplained RSAs are due to immunologic causes. The immunological risk to the developing embryo is not great until the time of implantation when. The major tissue confronting the motherâ??s immune system is the placental villous trophoblast. Trophoblast is not sensible to lysis by NK cells, TNF-a or macrophages, but may be killed by lymphokine activated NK cells (LAK) and may undergo apoptosis in response to TNF-a and/or IFN-g in vitro. The two most commonly used treatments for RSA are intravenous immunoglobulin (IVIg) and alloimmunization with partnerâ??s leukocytes (LIT). We promote vitamin D3 as new immunomodulatory agent in treatment of RSA. Different mechanisms have been proposed to account for the immunosuppressive effect of 1a,25-dihydroxy-vitamin-D3 (VD3). Portion of the VD3 activity involves the downregulation of IL-2, IFN-g and TNF-a genes transcription. Because immunomodulatory effects of VD3 are very similar like as effects of IL-10, acting of VD3 in immunotherapy of RSA or preeclamptic, eclamptic and PIH syndrome, is very reasonable. Our protocols considered using of VD3 as immunotherapy or adjuvant therapy in combination with classic immunotherapies of RSA.
Failure of Anti-tumor Immunity in Mammals - Evolution of the Hypothesis
Ivan Bubanovic1 and Stevo Najman2
1Department of Obstetrics and Gynecology â?? â??Medica Centerâ?? - Nis, Serbia and Montenegro, 2Institute for Biology, University Medical School â?? Nis, Serbia and Montenegro
Acta Biotheoretica, 2004;52(1):57-64.
ABSTRACT
Observations on the morphological and functional similarity between embryonic or trophoblast tissues and tumors are very old. Over a period of time many investigators have created different hypotheses on the origin of cancerogenesis or tumor efficiency in relation to the host immune system. Some of these ideas have been rejected but many of them are still current. A presumption of the inefficiency of anti-tumor immunity in mammals due to the high similarity between trophoblast and embryonic cells to tumor cells is very real. The mechanisms for the escape of tumors from the immune response are very similar to the mechanisms for the escape of a fetoplacental unit from the maternal immune response. The similarity between these two mechanisms is so great that any randomness must be banished. At the same time, an incidence of malignant tumors and the types of more frequent tumors in non-mammalian vertebrates is significantly different to that in mammals. Lastly, the mechanisms of anti-tumor immunity in mammals are substantially different from the mechanisms of anti-tumor immunity in other classes of vertebrates. These facts indicate that the immune system of mammals during anti-tumor immune response is tricked by the similarity between tumor cells and trophoblast or other placental cells. From this aspect, our conclusion is that anti-tumor immunity failure in mammals can be defined as an immunoreproductive phenomenon, which is developed under the evolutionary pressure of autoimmunity and reproductive effectiveness.
The hypothesis was presented on the
23rd Annual Meeting of the American Society for Reproductive Immunology.
New Haven, Connecticut, USA. (June 18-22, 2003).
Am J Reprod Immunol. 49(6):329-372, Abstract No 49; p.:351.
New Immunomodulatory Treatment for Infertile Men with Antisperm Antibodies
1Ivan Bubanovic, 2Stevo Najman, 3Slobodan Kojic
1Department of Obstetrics
and Gynecology Medica Centre - Nis, Serbia and Montenegro
2Institute for Biology, University Medical School - Nis, Serbia and
Montenegro
3Department of Obstetrics
and Gynecology - Medical Centre - Paracin, Serbia and Montenegro
Download .pdf version of the full text article
Fertility and Sterility, 2004; 81(3):S7-31: pp. 20.
American Journal of Immunology 1(4): 130-134, 2005
ABSTRACT
Possible causes of subfertility or infertility in humans as well as in other species are poorly defined, but one important category may be immunological disease mediated by antisperm antibodies (ASA). In this study, blood sera from 35 infertile men of different age with ASA positive ELISA test were examined for the serum level of ASA before and after treatments with 1a,25-dihydroxy-Vitamin-D3 and Dexamethasone. We observed 18 infertile men treated with Vitamin-D3/Dexamethasone protocol during three months, 9 infertile men treated with Dexamethasone only during three months and 8 infertile men without any treatment. All selected patients showed poor parameters of spermogram and high level of ASA serum concentration (>75 U/ml). Serum concentration of ASA in non-treated group (312.6 U/ml), Dexamethasone only treated group (288.0) and Vitamin-D3/Dexamethasone treated group (123.6 U/ml) are significantly different. Serum level of ASA in Vitamin-D3/Dexamethasone treated group was significant less as compared to the level before the treatment (P<0.01). Vitamin D3 and Dexamethasone treatment probably have suppressive effects in relation to antibody production, co-stimulatory molecules expression, immune cells communications and profile of cytokine network. Because the protocol is completely new, this is the first study of Vitamin D3 and Dexamethasone treatment concerning the suppression of ASA production.
The results were presented on the
52nd annual meeting and postgraduate course of the Pacific Coast Reproductive Society.
April 28-May 2, 2004. Rancho Mirage
Anti-tumor Immunity and Different Way of Clustering of LMP/TAP/MHC Genes in Vertebrates
1Ivan Bubanovic, 2Stevo Najman
1Department of Obstetrics and Gynecology â?? â??Medica Centreâ?? - Nis,
Serbia and Montenegro
2Institute for Biology, University Medical School â?? Nis, Serbia and
Montenegro
ABSTRACT
Class I and class II MHC genes have been identified in most of the jawed vertebrate taxa, including cartilaginous fish, bony fish, amphibian, reptiles, birds and mammals. Unlike to mammals, in all investigated bony fish species, the classical class I and class II MHC genes are not linked and even are found on different chromosomes. Linking and clustering of the class I and class II MHC genes is not the only phenomenon clearly detected in the evolution of immune system from cartilaginous fish to mammals. In all non-mammalian classes the LMP/TAP genes are highly conserved within class I genes region, while these genes are conserved within class II genes region only in mammals. Today we know that LMP/TAP genes in mammals have crucial role in peptide processing for presentation within class I molecules, as well as in anti-tumor immunity. From these reasons, differences in clustering of LMP/TAP/MHC genes can be responsible for differences in mechanisms and efficacy of anti-tumor immunity in non-mammalian vertebrates compared to same mechanisms in mammals. Also, differences in cytokine network and anti-tumor antigens presentation within classes of vertebrates can be explained with peculiarity of LMP/TAP/MHC genes clustering.
The hypothesis was presented on the 7th International Symposium on Predictive Oncology:
Link to Impact of Biotechnology on Predictive Oncology & Intervention Strategies
Nice, France - February 7 - 10, 2004
and
24th Annual Meeting of the American Society for Reproductive Immunology (ASRI)
St. Louis, Missouri, USA - June 3-6, 2004
Autoimmunity and Alloimmunity as by Products of Adaptive Immunity and Sources of Anti-tumor Immunity Failure
1Ivan Bubanovic, 2Stevo Najman
1Department of Obstetrics and Gynecology "Medica
Centre" - Nis,
Serbia and Montenegro
2Institute for Biology, University Medical School -
Nis, Serbia and
Montenegro
ABSTRACT
In all vertebrates, a functional immune system is able to react against foreign antigens while remaining unresponsive to self-antigens. This self-tolerance is acquired and maintained by combination of central and peripheral tolerances. There are evidences that many auto-immune diseases and alloimmunity are characteristic of vertebrates and that they are associated with MHC molecules. The protective mechanisms which evolved in response to the auto-immunity-imposed evolutionary pressure or, more precisely, co-evolved with the phenomenon of auto-immunity, are related to various forms of immune tolerance, strong and multileveled control immunomodulatory and suppressive factors like sex hormones, IL-10, TGF-b, Th2 activity, apoptosis and/or anergy of self reactive clones, blood-barrier sequestration of â??selfâ?? molecules, cells, tissues and organs. In addition, with the appearance of viviparity and placentation as possible models of natural allotransplantation, the phenomenon of alloimmunity acquired the role of factor of selection pressure. Alloimmunity can be another by-product of evolution of the adaptive immunity which emerged under selection pressure of microbes and â??latentlyâ?? accumulated enormous strength. With the emergence of viviparous mammals, the further evolution of adaptive immunity and reproduction became closely associated with alloimmunity as a new powerful factor of selection pressure in direct connection with reproductive efficacy. As in the case of autoimmunity, selection pressure of alloimmunity caused the emergence of fine mechanisms for the control of immune reaction on one hand and absence of expression of MHC molecules on placental tissues, on the other â?? except for monomorphic and low-polymorphic MHC class Ib molecules. Controlling mechanisms for the prevention of auto-immunity are very similar to mechanisms of immunotolerance in pregnancy and mechanisms of tumor escape. Therefore, controlling/protective mechanisms of immunotolerance in pregnancy could represent a more effective and sophisticated advancement of the controlling mechanisms for the prevention of auto-immunity. In addition, there are large body of data that same or very similar controlling/protective mechanisms are included in tumor escape.
The hypothesis was presented on the 7th International Symposium on Predictive Oncology:
Link to Impact of Biotechnology on Predictive Oncology & Intervention Strategies
Nice, France - February 7 - 10, 2004
and
24th Annual Meeting of the American Society for Reproductive Immunology (ASRI)
St. Louis, Missouri, USA - June 3-6, 2004
Diversification of Cytokines Across
Vertebrate Evolution and Anti-tumor Immunity Failure
1Ivan Bubanovic, 2Stevo Najman
1Department of Obstetrics and Gynecology "Medica
Centre" - Nis,
Serbia and Montenegro
2Institute for Biology, University Medical School -
Nis, Serbia and
Montenegro
ABSTRACT
Cytokines have been identified and studied extensively in mammals, but little is known about their presence in other vertebrate groups. The phylogenetic analysis does not reveal any clear evidence of orthology of lower vertebrates and human cytokines. Although the divergence of the subfamilies began before the fish-tetrapod split, much of the divergence within the subfamilies took place separately in different vertebrate groups, especially in mammals. However, the existence of chemokine receptors in the lamprey indicates that chemokines are apparently also present in the Agnatha. Many cytokines and their receptors, like most molecules of the immune system, tend to evolve rapidly, so that it has not been a simple task to isolate their ancestor genes and proteins. Cytokine homologs are found within jawless vertebrates, although no cytokine or cytokine receptor genes have been sequenced in cartilaginous fish except newly discovered IL-1b-like gene. Several cytokines, including IFNs, IL-1, IL-2, IL-6, IL-8 and TGF-b, have been identified in birds, reptiles, amphibians, and bony fish. Although cytokines with vertebrate counterparts are likely to be present in invertebrates, no gene has been cloned that leaves a large gap in our knowledge of cytokine evolution. The oldest classes of vertebrates are characterized by a small number of cytokines, probably tracing origin from regulatory factors whose primary role was not associated with immune mechanisms. During vertebrate evolution, this number grew dramatically, as well as the parallel growth number of regulatory cells and their function in the controlling of immune reaction. In lower vertebrates, cytokine network of the immune reaction consists mainly of the cytokines which are in mammals called the pro-inflammatory cytokines. Clearly defined, â??specializedâ?? and strong immunosuppressive cytokines have been only found in mammals, although the role of anti-inflammatory cytokines in lower vertebrates could be associated with the TGF superfamily. Even in birds, whose immune system is most similar to mammalian, cytokines like IL-4 and IL-10 have not been clearly identified. In conclusion, evolution of the adaptive immunity is associated with emergence of auto-immunity and alloimmunity/reproductive efficacy as by-products of "self/non-self" recognition. With auto-immunity and alloimmunity (especially in mammals) as new evolutionary forms of selection pressures, emergence of strong control mechanisms of immune reaction is not surprisingly. In this regard, diversification of cytokines across evolutionary time and emergence of suppressive cytokines, as well as other control mechanisms of immune reaction, can be defined as another by-product of adaptive immunity. In addition, there are significant correlations between strength of adaptive immunity and number of cytokines in different classes of vertebrates. Finally, these relations can be associated with anti-tumor immunity failure and source of different incidences of neoplasms in vertebrates.
The hypothesis was presented on the
Link to 24th Annual Meeting of the American Society for Reproductive Immunology (ASRI)
St. Louis, Missouri, USA - June 3-6, 2004
RANKL/RANK/Osteoprotegerin System as Novel Therapeutic Target in the Treatment of Primary Bone Tumors and Osteolytic Metastases
Z. Andjelkovic1, V. Katic2, D. Mihailovic2, A. Petrovic2, I. Bubanovic3
1Institute of Histology, Medical Faculty Pristina, Kosovska Mitrovica, 2Institute of Pathology, Medical Faculty Nis, Nis, 3Ob/Gyn department, Medical Center, Nis, Serbia & Montenegro
Correspondence to: Dr. Zlatibor Andjelkovic, Maglajska 8, 18000 Nis,Serbia & Montenegro; E-mail: zlatibor@bankerinter.net
Archive of oncology,
2004;12(2):112-114.
ABSTRACT
Primary bone tumors and cancers that metastasize to bone require osteoclastic activity to release tumor-supportive growth factors from bone tissue. A number of systemic and locally acting factors are known to influence osteoclast formation, fusion, activation, and survival. Recently, two critical extracellular regulators of osteoclast differentiation and activation have been identified: receptor activator of nuclear factor (NF-kappaB) ligand (RANKL) and osteoprotegerin (OPG). RANKL is a tumor necrosis factor (TNF)-related cytokine that stimulates osteoclast differentiation from hematopoietic precursor cells and activation of mature osteoclasts. RANKL activates its specific receptor, receptor activator of NF-kappaB (RANK), located on osteoclasts, chondrocytes and dendritic cells. Binding of the RANK ligand to its receptor and osteoclastogenesis are prevented by osteoprotegerin, a decoy receptor produced by osteoblasts and marrow stromal cells. The balance between RANKL and OPG is of major importance in bone homeostasis. Disorders of the RANKL/RANK/OPG system have been linked to several human diseases, including primary bone tumors, skeletal metastases, and hypercalcemia of malignancy. The discovery and characterization of RANKL, RANK and OPG and subsequent studies have changed the concepts of bone metabolism and may form the basis of innovative therapeutic strategies. Novel treatment strategies for bone tumors are emerging based on blockade of the RANKL/RANK interaction. The advantage of these strategies is their potential to selectively target tumor cells. Combining these new strategies with currently available treatments such as chemotherapy and radiation therapy is under investigation, with promising results.
Diversification of Cytokines Across Vertebrate Immune System Evolution, Reproductive Efficacy and Tumor Escape
1Ivan Bubanovic, 2Stevo Najman
Download Full Text of the article (pdf)
All abstracts - Thursday - Click Here
1Department of Obstetrics and Gynecology "Medica
Centre" - Nis,
Serbia and Montenegro
2Institute for Biology, University Medical School - Nis, Serbia and
Montenegro
Full text of
the article you can find in the Collection of Free Papers presented at the 12th
International Congress of Immunology and 4th annual Conference of FOCIS
Volume:
Autoimmunity, Genetic and Degenerative Disorders, Malignancies, and
Transplantation; pp:369-374.
Clinical and Investigative Medicine, 2004;Th53.15: p.163.
ABSTRACT
Cytokines have been identified and studied extensively in mammals, but little is
known about their presence in other vertebrate groups. Although the divergence
of cytokine subfamilies began before the fish-tetrapod split, much of the
divergence within the subfamilies took place separately in different vertebrate
groups. Many cytokines and their receptors, like most molecules of the immune
system, tend to evolve rapidly, so that it has not been a simple task to isolate
their ancestor genes. Cytokine homologs are found within jawless vertebrates,
although no cytokine or cytokine receptor genes have been sequenced in
cartilaginous fish except newly discovered IL-1b-like gene. Several cytokines,
including IFNs, IL-1, IL-2, IL-6, IL-8 and TGF-b, have been identified in birds,
reptiles, amphibians, and bony fish. During vertebrate evolution, this number
grew dramatically, as well as the parallel growth number of regulatory cells and
their function in the controlling of immune reaction. In lower vertebrates,
cytokine network of the immune reaction consists mainly of the cytokines which
are in mammals called the pro-inflammatory cytokines. Clearly defined,
specialized and strong immunosuppressive cytokines have been only found in
mammals, although the role of anti-inflammatory cytokines in lower vertebrates
could be associated with the TGF superfamily. Even in birds, whose immune system
is most similar to mammalian, cytokines like IL-4 and IL-10 have not been
clearly identified. In conclusion, evolution of the adoptive immunity is
associated with emergence of auto-immunity and alloimmunity/reproductive
efficacy as by-products of self/non-self recognition. With auto-immunity and
alloimmunity (especially in mammals) as new evolutionary forms of selection
pressures, emergence of strong control mechanisms of immune reaction is not
surprisingly. In this regard, diversification of cytokines through evolution and
emergence of suppressive cytokines, as well as other control mechanisms of
immune reaction, can be defined as another by-product of adoptive immunity. In
addition, there are significant correlations between strength of adoptive
immunity and number of cytokines in different classes of vertebrates. Finally,
these relations can be associated with anti-tumor immunity failure and source of
different incidences of neoplasms in vertebrates.
The hypothesis was presented on the
Link to 12th International Congress of Immunology & 4th Annual Conference of FOCIS
Montreal, Canada - July 18-23, 2004
Anti-Interleukin-10 Strategies in Treatment of Malignant Diseases
1Ivan Bubanovic, 2Stevo Najman
1Department of Obstetrics and Gynecology "Medica
Centre" - Nis,
Serbia and Montenegro
2Institute for Biology, University Medical School - Nis, Serbia and
Montenegro
Download the Abstract Book (pdf)
Paper No 83, page: 26; Download full program of the meeting.
ABSTRACT
Interleukin-10 (IL-10) is important cytokine for phenomena of tumor growth, escape and even carcinogenesis. This cytokine is essential for tumor cell proliferation because its neutralization decreases clonogenicity of malignant cells, whereas addition of recombinant IL-10 increases cell proliferation. IL-10 autocrine/paracrine loop plays an important role in the resistance of certain tumors to chemotherapeutic drugs. In addition, immunomodulatory/suppressive nature of IL-10 plays significant role in mechanisms of tumor escape from immune monitoring. Nevertheless, there is no clear anti-IL-10 strategy in treatment of malignant disease. In fact, there are a few hypotheses, and small number of experimental/clinical studies, that propose anti-IL-10 strategy in treatment of malignant diseases. For example, Ammonium Trichloro(dioxoethylene-o,o')tellurate (AS101) inhibits synthesis of tumor IL-10 on the transcriptional level. Therefore, AS101 treatment combined with chemotherapy may be effective in the treatment of certain malignancies. Another possibility is treatment of malignant patients by anti-IL-10 antibodies with unpredictable consequences and complications in relation to autoimmunity and immune complexes disease. The strategy that we suggest is based on extracorporeal blood filtration/purification method with a view to removing IL-10 molecules from patientâ??s blood by anti-IL-10 antibodies attached on the filter walls. The present strategy provides a method for enhancing an immune response in tumor sufferers to facilitate the elimination of IL-10 and/or other immunosuppressive cytokines and other molecules. The method involves the removal of immune system inhibitors from the circulation of the tumor sufferers, thus, enabling a more vigorous immune response to the tumor. Particularly useful in the strategy is an absorbent matrix composed of an inert, biocompatible substrate joined covalently to a binding partner, such as antibody, capable of specifically binding to the IL-10.
The strategy was presented on the
Link to Cytokines in Cancer and Immunity
International Cytokine Society and
International Society for Interferon and Cytokine Research
San Juan, Puerto Rico
-
October 21-25, 2004
and
8th International Conference on Human Leukocyte
Differentiation Antigens
34th Annual Scientific Meeting of the Australasian Society for Immunology
Adelaide Convention Centre, Australia - December
12-16, 2004Is the Oncogenesis Epigenetic Induced Alternative Way for Cell Survival?
1Ivan Bubanovic, 2Stevo Najman
1Department of Obstetrics and Gynecology "Medica
Centre" - Nis,
Serbia and Montenegro
2Institute for Biology, University Medical School - Nis, Serbia and
Montenegro
ABSTRACT
Microevolution of tumors is accompanied by all, or almost all, elements that characterize evolution in the Darwinian sense. The evolution of tumors progress on a time scale of months and years within a limited population of altered cells, involving all the phenomena observed in the long-term evolution of species. These phenomena include random changes in the genome of tumor cells, various forms of selection pressure and selection of tumor cells. Mutations of key genes endow tumor cells with a selective growth advantage and, in the presence of an unstable genome, these cells further mutate and undergo progressive "clonal evolution". Albeit this model of tumor survival is widely accepted, there is possibility that emergence of "first" altered cell generation follow same axioms as mentioned phenomena of tumor growth and escape. To that effect, shifting of a normal cell to the tumor cells might bi explained as activation of adaptive mechanisms for cell survival. Thanks to large genetic potential and searching for "better solution", the "endangered cell" or cell under abnormal conditions/selection pressure may wend to malignant alteration as an alternative way for survival. For example, epigenetic factors such as chemical distresses or virus-infection may activate the silenced genes that are responsible for malignant alteration. In vertebrates, evolutionary accumulation of genetic potentials is associated with phenomena of epigenetic induced adaptation and ability of species for survival in different conditions. In the same way, shifting of the cell from normal to altered might be conceived as an epigenetic induced adaptation for cell survival, as well as mechanism of tumor escape.
The hypothesis was presented on the
Adelaide Convention Centre, Australia
â?^ December 12-16, 2004and
FOCIS ANNUAL MEETING, May 12-16, 2005 â?^ Westin Copley Place, Boston, Massachusetts. Sa2.93.
Comparative Oncology and Comparative Tumor Immunology
1Ivan Bubanovic, 2Stevo Najman
1Department of Obstetrics and Gynecology â?? â??Medica Centreâ?? - Nis,
Serbia and Montenegro
2Institute for Biology, University Medical School â?? Nis, Serbia and
Montenegro
Full Text of the article (pdf)
Journal of Biological Sciences, 2005; 5(2):114-118.
ABSTRACT
Comparative oncology is a branch of comparative pathology that is relatively
new biomedical discipline. The need for a comparative research into tumors
across different groups of living beings has arisen from a relatively old
notion that most of multicellular organisms may develop tumors. This
apparently very simple fact indicate the possible nature of tumor growth,
which can be associated with the basic features of the cells of
multicellular organisms such as the division, development, growth and
differentiation of cells and tissues. Regarding this, tumor growth is
commonly defined as a fundamental disorder in the regulation of cell
division, growth, differentiation and cell socialization. In all
vertebrates, neoplasia is a disease in which genetically altered cells
escape from the normal cell-cycle regulation and monitoring of the immune
system. This results in a persistent, expanding or infiltrating growth
without control and the architecture of the normal tissue. Concerning the
facts that mechanisms of cell sociability control and anti-tumor immune
monitoring might be different in different group of animals, especially, in
different classes of vertebrates, development of disciplines such as
comparative oncology and comparative tumor immunology can be of great
scientific importance.
Different Way of LMP/TAP/MHC Genes Clustering in Vertebrates, Viviparity and Anti-tumor Immunity Failure
1Ivan Bubanovic, 2Stevo Najman
1Department of Obstetrics and Gynecology â?? â??Medica Centreâ?? - Nis,
Serbia and Montenegro
2Institute for Biology, University Medical School â?? Nis, Serbia and
Montenegro
Link to the Journal - Integrative Biosciences
Download .pdf version of the article
Integrative Biosciences, 2005; 9:1-7.
ABSTRACT
Class I and class II MHC genes have been identified in most of the jawed vertebrate taxa. Unlike to mammals, in all investigated bony fish species, the classical class I and class II MHC genes are not linked and even are found on different chromosomes. Linking and clustering of the class I and class II MHC genes is not the only phenomenon clearly detected in the evolution of immune system from cartilagofish to mammals. In all non-mammalian classes the LMP/TAP genes are highly conserved within class I genes region, while these genes are conserved within class II genes region only in mammals. Today we know that LMP/TAP genes in mammals have crucial role in peptide processing for presentation within class I molecules, as well as in anti-tumor immunity. From these reasons, differences in clustering of LMP/TAP/MHC genes can be responsible for differences in mechanisms and efficacy of anti-tumor immunity in non-mammalian vertebrates compared to same mechanisms in mammals. Also, differences in cytokine network and anti-tumor antigens presentation within classes of vertebrates can be explained with peculiarity of LMP/TAP/MHC genes clustering.
Origin and Evolution of Viruses: Escaped DNA/RNA Sequences as Evolutionary Accelerators and Natural Biological Weapons
1Ivan Bubanovic, 2Stevo Najman, 3Zlatibor Andjelkovic
1Department of Obstetrics and Gynecology â?? â??Medica Centreâ?? - Nis, Serbia and Montenegro, 2Institute for Biology, University Medical School â?? Nis, Serbia and Montenegro, 3Institute of Histology, Medical Faculty Pristina, Kosovska Mitrovica
Medical Hypotheses, 2005;65:868-872
ABSTRACT
Knowledge of the origin and evolution of viruses could provide a better understanding of a number of phenomena in the field of evolution such as the origin and development of multi-cellular organisms, the rapid diversification of species over the last 600-700 million years and the lack of transitional forms in the evolution of species (missing links) etc. One of the possible effects of escaped DNA/RNA sequences or viruses on the evolution of multi-cellular organisms, especially vertebrates, could be the phenomenon of horizontal transmission and dissemination of genes. Interestingly, if so, this effect could be considered as a model of primeval and natural genetic engineering. Other possible links between the evolution of multi-cellular organisms and viruses are connected with the fact that viruses represent the source of different forms of selective pressure such as epidemics of infectious diseases, autoimmunity, malignant alteration, reproductive efficiency etc. At the same time, these two models of â??long-term evolutionary relationsâ?? could represent â??key factorsâ?? in the evolution between viruses and multi-cellular organisms. The capability of a genome to produce and emit DNA/RNA sequences or de novo created viruses which can be a vector of genes horizontal transmission and/or cause selective pressure on concurrent or predator species gives a new characteristic to viruses â?? the possibility of their acting as natural biological weapons. Finally, possibly evolutionary advantages of this genome capability could be one of explanations for the phenomena such as genome instability and its ability to emit DNA/RNA sequences and/or de novo created viruses, as well as evolutionary conservation of this unique phenomena.
Adipose tissue in age-related involution of the thymus
Andjelkovic Z, Vitkovic L, Savic S, Lestarevic S, Mitic BN, * Bubanovic I
Institute of Histology, Medical Faculty Pristina, Kosovska Mitrovica, *Department of Obstetrics and Gynecology "Medica Centre" - Nis, Serbia and Montenegro
Anali, 2005;8:83-86.
ABSTRACT
Age-associated thymic atrophy is a key event preceding the inefficient functioning of the immune system, resulting in a diminished capacity to generate new T-cells. Thymic involution results in changes to the thymic architecture. Initially, the perivascular space is enlarged by lymphocytic infiltration, but during the aging process adipose tissue replaces these lymphocytes. Adipose tissue is now recognized to be a multifunctional tissue; in addition to the central role of lipid storage, it has an endocrine function secreting hormone leptin, and various signal substances (cytokines and growth factors) collective named adipokines. These signal substances have important roles in metabolism, reproduction, and immunity. Some inflammatory cytokines and growth factors secreted by adipocytes may influence thymocyte development, epithelial cell growth and function, and organ atrophy. A greater understanding of the possible role of adipocytes in thymic physiology may provide insight into strategic therapies to improve thymopoiesis within the aging host.
Auto-immunity as Evolutionary by Product of Adoptive Immunity and Source of Anti-tumor Immunity Failure
Ivan Bubanovic
Department of Obstetrics and Gynecology "Medica Centre" - Nis, Serbia and
Montenegro
Link to the Journal - International Journal of Cancer Research
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International Journal of Cancer Research, 2005; 1(2): 81-86.
ABSTRACT
One of the biggest threats to survival is infection, so that the immune system is under permanent and strong evolutionary pressure to be highly responsive. By tracing the evolution of the invertebrate immune system, it can be seen that it largely followed the "classical" model based on bi-directional "predator-prey" relationships. Similarly, the evolutionary emergence of MHC system and the mechanisms of immune recognition in vertebrates came as a direct result of a microbe-exerted selection pressure. The new possibilities gave rise to new conveniences and brought about certain risks in the new forms, like auto-immunity, allo-immunity and reproductive efficacy. To that effect, the evolutionary emergence of the MHC has enabled a more effective defence from intracellular parasites, such as viruses. However, the whole complex of processing/presenting/recognizing of antigens could be closely related to the auto-immunity as a by-product of the evolution of MHC system and adoptive immunity. On the other hand, tumor development is frequently accompanied by the immune response against "self" and altered antigens expressed by tumor cells, because these antigens are the most prevalent molecules recognized by the immune system. The activation of the auto-immune process in parallel with an effective anti-tumor response could mean the failure of protective control mechanisms of the immune reaction that may be responsible for the prevention of auto-immune diseases. At the same time, the activation of suppressor/modulatory mechanisms possibly accompanied by the activation of anti-tumor auto-immune-like immune response could be a factor of anti-tumor immunity failure in all vertebrates.