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New  book: Origin of anti-tumor immunity failure in mammals

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POREKLO SLABOSTI ANTI-TUMORSKOG IMUNSKOG ODGOVORA KOD SISARA I NOVE MOGUCNOSTI ZA IMUNOTERAPIJU

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Ivan Bubanovic

Ginekolosko-akusersko odeljenje, Zadravstveni centar - Gnjilane

Medical Hypotheses, 2003;60(2):152-158.

Sazetak

Postoji puno dokaza da tumori mogu biti imunogenicni. Tumorske celije veoma cesto eksprimiraju antigene u prepoznatljivoj formi za imunski sistem domacina, ali najcesce bez posledica po tumorski rast i progresiju bolesti. Ovo je dokazano na mnogim eksperimentalnim modelima i u razlicitim eksperimentalnim uslovima. Osnovni mehanizmi slabosti anti-tumorskog imunskog odgovora kod sisara su veoma slicni mehanizmima slabosti anti-trofoblastnog imunskog odgovora u trudnoci. Slicnost ovih mehanizama je tako velika, da je svaka slucajnost iskljucena. Mehanizmi anti-tumorskog imunskog odgovora kod sisara se sustinski razlikuju u odnosu na mehanizme anti-tumorskog imunskog odgovora kod ostalih klasa kicmenjaka. Osim toga, incidenca malignih tumora kod nesisarskih klasa kicmenjaka je znacajno niza nego kod sisara. Najcesci tipovi malignih tumora kod nesisaskih klasa kicmenjaka se takodje znacajno razlikuju u odnosu na tipove najcescih malignih tumora kod sisara. Ovi podaci ukazuju na mogucnost da je imunski sistem sisara tokom anti-tumorskog odgovora zavaran slicnoscu izmedju tumorskih i trofoblastnih ili drugih posteljicnih celija. Sve ovo anti-tumorskom imunskom odgovoru sisara daje karakter imunoreproduktivnog fenomena i otvara, do sada neistrazene mogucnosti za kreiranje novih imunoterapeutskih procedura.

(Zbornik radova XV Jugoslovenskog simpozijuma o fertilitetu i sterilitetu, Beograd, 2002. str.: 262-266.)

INDUKCIJA TIMUSNE TOLERANCIJE KAO MOGUCNOST PREVENCIJE REKURENTNIH SPONTANIH POBACAJA

Ivan Bubanovic

Ginekolosko-akusersko odeljenje, Zadravstveni centar - Gnjilane

Medical Hypotheses, 2003;60(4):520-524.

Sazetak

Najvazniji procisi tokom kojih imunski sistem postaje tolerantan na sopstvene proteine ukljucuje deleciju tzv. self-reactivnih u timusu i/ili inhibiciju specificnih Th1 celisjkih klonova. Proces uspostavljanja specificne imunske tolerancije dva selekciona mehanizma poznata kao pozitivna i negativna selekcija. Timus je antigenski "privilegovan" organ, uglavnom zbog postojanja krvno-timusne barijere. Veliki broj istrazivaca je pokazao da intratimusna inokulacija antigena rezultuje indukcijom specificne tolerancije. Embrion/fetus i posteljica predstavljaju alotransplantat, koji majka mora tolerisati do kraja trudnoce. Iz ovih razloga, danas postoji veliki interes za rasvetljavanjem imunskih mehanizama koji ucestvuju u razvijanju fenomena rekurentnih spontanih pobacaja (RSA). Neke studije govore da je vise od 50% RSA posredovano imunskim mehanizmima. Priroda ovog poremecaja je najverovatnije sadrzana u disbalansu Th1/Th2 odnosa. Terapija RSA imunizacijom zene paternalnim leukocitima (PLI) se upravo bazira na contra-shiftu Th1/Th2 odnosa. PLI procedura indukuje neku vrstu periferne tolerancije na fetalne/trophoblastne antigene, ali problem centralne tolerancije ostaje otvoren. Intratimusna inokulacija fetalnih ili paternalnih (kao sto su leukociti, timusne dendriticne celije, trofoblastne celije) ili paternalnog seta MHC molekula, moze usloviti centralnu specificnu toleranciju i mogla bi biti osnava za terapiju RSA.

SLABOST KRVNO-TIMUSNE BARIJERE KAO MEHANIZAM RAZVIJANJA SLABOSTI ANTI-TUMORSKOG IMUNSKOG ODGOVORA I GRAVIDARNE IMUNOTOLERANCIJE

Ivan Bubanovic

Ginekolosko-akusersko odeljenje, Zadravstveni centar - Gnjilane

Medical Hypotheses, 2003:60(3):315-320.

Sazetak

Najvazniji procesi koji ucestvuju u razvijanju tolerancije na sopstvene proteine ukljucuje deleciju self-reaktvnih klonova u timusu, ali klonalna delecija nije jedini mehanizam timusne tolerancije. Postoje dokazi da intratimusna antigenska ekspresija rezultuje i anergijom specificnih Th1 klonova na periferiji. Krvno-timusna barijera je najvaznija struktura za prevenciju nezeljene penetracije antigena u timus. Nepropustljivost ove barijere sprecava uspostavljanje timusne (centralne) tolerancije na nezeljene antigene, kao sto su mikrobi i tumorske celije. Medjutim, i pored ovoga jedan od najvaznijih mehanizama, koji ucestvuju u razvijanju slabosti anti-tumorskog imuniteta i gravidarne imunotolerancije, je sadrzan u anergiji Th1 celija i dominaciji Th2 celija. Mnogi mehanizmi ucestvuju u remecenu balansa izmedju Th1 i Th2 celija u trudnoci i kod nosioca tumora, ali jedna od verovatnih mogucnosti je slabost ili slabljenje krvno-timusne barijere. Posledice povecane propustljivosti krvno-timusne barijere mogu biti penetracija trofoblastnih ili tumorskih antigena u timus, klonalna delecija, anergija i specificna imunska tolerancije. Krvno-timusna barijera je promenljiva struktura u anatomskom i funkcionalnom smislu, tako da pod odredjenim uslovima, strani antigeni mogu proci kroz krvno-timusnu barijeru. Mogucnost da faktori kao sto su hormoni, citokini i neuromedijatori mogu uticati na propustljivost krvno-timusne barijere i ucestvovati u razvijanju slabosti anti-tumorskog imuniteta i gravidarne imunotolerancije je realna ali realtivno neistrazena.

RASKRSNICE EKSTRATIMUSNIH LIMFOCITNIH MATURACIONIH PUTEVA

Ivan Bubanovic

Ginekolosko-akusersko odeljenje, Zadravstveni centar - Gnjilane

Medical Hypotheses, 2003;61(2):235-239.

Sazetak

Vecina T celija lokalizovanih u perifernim limfoidnim organima je zavisna od timusa u pogledu pravilne diferencijacije i maturacije. Samo mali broj perifernih T limfocita je timus nezavisna. Ove celije prolaze kroz ekstratimusne maturacione procese, da bi na kraju postali zreli limfociti. Neki podaci sugerisu da mehanizam ekstratimusne maturacije limfocita (eTML) ukljucuje migraciju, proliferaciju, diferencijaciju i selekciju limfocita, kao i timusni put limfocitne maturacije. Starenjem i progresijom timusne involucije, ili u slucajevima akcidentalne involucije timusa eTML dobija na znacaju. T limfociti koji poticu iz eTML verovatno mogu da polarizuju akciju timus zavisnih limfocita ili ucestvovati u imunskoj reakciji kao antigen-destruktivni ili antigen-protektivni cinioci. Iz ovoga proizilazi da eTML moze biti izvor self-reaktivnih limfocita ili celija koje ucestvuju u razvijanju slabosti anti-tumorskog imunskog odgovora i gravidarne imunotolerancije. Rezultati eTML verovatno nisu unapred odredjeni, vec zavise od mnogih faktora i mikrosredinskih trenutnih okolnosti. Faktori kao sto su citokini, prostaglandini, mikrobi, MHC molekuli, hormoni, Fas ligandi, heat shock proteins, fenotip dendriticnih celija i APCs, verovatno mogu usmeriti pravac odvijanja eTML. Definitivni smer aktivnosti limfocita poreklom iz eTML procesa, prevashodno je rezultat mikrosredinskih relacija i interakcije mnogih faktora. Hipoteza da mikrobi, narocito virusi, mogu biti promotori ekstratimusnih self-reaktivnih limfocita je realna, kao i hipoteza da limfociti iz procesa eTML i njihovi produkti mogu ucestvovati u mehanizmima slabosti anti-tumorskog imuniteta, gravidarne imunotolerancije i mehanizmima tolerancije transplantiranih tkiva i organa.

1a,25-dihydroxy-vitamin-D3 kao nova mogucnost imunoterapije rekurentnih spontanih pobacaja

Ivan Bubanovic

"Medica Centar" - Nis

Medical Hypotheses, 2004;63(2):250-253.

Sazetak

Rekurentni spontani pobacaji (RSA) su znacajan zdravstveni problem koji se srece kod 2-5% reproduktivno aktivnih zena. Postoji misljenje da je oko 80% RSA posredovano imunskim faktorima. Rizik za odbacivanjem embriona u razvoju nije veliki u vreme implantacije, ali se znacajno povecava u vreme trofoblastne invazije decidualno izmenjenog endometrijuma. U normalnim okolnostima trofoblast nije osetljiv na aktivnost NK celija, TNF-a i makrofaga. Medjutim, ako su NK celije aktivirane citokinima kao sto su IL-2, TNF-a i IFN-g, ove celije se transformisu tzv. LAK celije (Lymphokine Activated Cells) i veoma su uspesne u liziranju trofoblasta. Dve najcesce koriscene metode za lecenja RSA su tretman imunoglobulinima (IVIg) i imunizacija partnerovim ili uopste alogenim leukocitima. Mi smo promovisali vitamin D3 kao novu mogucnost imunoterapije RSA. Deo imunomodulatorne aktivnosti VD3 je sadrzan u inhibiciji sinteze i sekrecije citokina kao sto su IL-2, TNF-a i IFN-g na nivou transkripcije gena za ove citokine. Zbog toga sto su mehanizmi akcije VD3 veoma slicni efektima IL-10, upotreba VD3 u lecenju RSA, PIH sindroma, preeklampsije i eklampsije je veoma razumna i logicna. Nasi protokoli sadrze VD3 kao mono-imunoterapijski agens ili adjuvantni preparat u kombinaciji sa klasicnim imunoterapijskim pristupom.

Centar za naucne informacije
Narodna biblioteka Srbije
Skerliceva 1, Beograd

Failure of Anti-tumor Immunity in Mammals - Evolution of the Hypothesis

¹Ivan Bubanovic and ²Stevo Najman

¹Department of Obstetrics and Gynecology – “Medica Center” - Nis, Serbia and Montenegro

²Institute for Biology, University Medical School – 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 N^o 49; p.:351.

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Imunomodulatorni tretman infertilnih muskaraca sa povisenim vrednostima anti-spermatozoidnih antitela

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¹Ivan Bubanovic, ²Stevo Najman, ³Slobodan Kojic

¹Department of Obstetrics and Gynecology – “Medica Center” - Nis, Serbia and Montenegro
²Institute for Biology, University Medical School – Nis, Serbia and Montenegro
³Department of Obstetrics and Gynecology – Medical Center – Paracin, Serbia and Montenegro

Fertility and Sterility, 2004; 81(3):S7-31: pp. 20.

American Journal of Immunology  1(4): 130-134, 2005

Zbornik radova XLVIII Ginekolosko-akuserske nedelje SLD, Beograd. str.:273-278.

REZIME

Autoimunska oboljenja muskog genitalnog trakta udruzena sa anti-spermatozoidnim antitelima (ASA) i njihova povezanost sa infertilnoscu su predmet intenzivnog proucavanja. Iako ne postoje sigurni dokazi da ASA mogu predstavljati uzrok infertiliteta, pouzdano se zna da su zapaljenjska oboljenja testisa, povrede, hirurske intervencije kao i oboljenja druge etiologije, udruzena sa autoimunskim orhitisom i porastom titra ASA u serumu i semenoj tecnosti. U nasoj studiji, serum 35 muskaraca iz neplodnih brakova je testiran (ELISA testom) na serumski nivo ASA pre i posle tretmana 1a,25-dihidroksi-vitaminom-D3 (VD3) i/ili deksametazonom. Osamnaest pacijenata je tretirano VD3 i deksametazonom (VD3D), devet pacijenata je tretirano samo deksametazonom, dok je osam pacijenata sacinjavalo kontrolnu grupu. Tretman VD3 i deksametazonom je trajao 30 dana, a sermski nivo ASA je testiran pre pocetka terapije i nakon 90 dana. Osnovni parametri spermograma su tako|e verifikovani pre pocetka terapije i nakon 90 dana. Serumski nivo ASA netretirane grupe pacijenata (312,6 U/ml), grupe tretirane samo deksametazonom (288,0 U/ml) i grupe pacijenata tretirane VD3D kombinacijom (123,6 U/ml) pokazao je statisticki znacajnu razliku. Serumski nivo ASA posle VD3D tretmana je znacajno nizi u odnosu na nivo ASA pre tretmana, sto nije slucaj sa ostale dve grupe pacijenata. Tretman VD3 i deksametazonom verovatno ima supresivni efekat u odnosu na produkciju antitela, ekspresiju ko-stimulatornih molekula, komunikaciju imunskih celija i profil citokinske mreze na sistemskom i mikrosredinskom nivou. Da li je snizavanje serumske koncentracije ASA praceno snizenjem koncentracije ASA u semenoj tecnosti kao i konacni efekti terapije na fertilnost pacijenata sa povisenim ASA, za sada nisu poznati.

The results were presented on the

52^nd annual meeting and postgraduate course of the Pacific Coast Reproductive Society.

April 28-May 2, 2004. Rancho Mirage • California, USA.

ID:/Article N^o: 943

Anti-tumor Immunity and Different Way of Clustering of LMP/TAP/MHC Genes in Vertebrates

¹Ivan Bubanovic and ²Stevo Najman

¹Department of Obstetrics and Gynecology – “Medica Center” - Nis, Serbia and Montenegro
²Institute for Biology, University Medical School – Nis, Serbia and Montenegro
 

American Journal Of Reproductive Immunology, 2004;51(6) pp.:401-441.

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:

Impact of Biotechnology on Predictive Oncology & Intervention Strategies

Nice, France • February 7 - 10, 2004

and

24^th 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 and ²Stevo Najman

¹Department of Obstetrics and Gynecology – “Medica Center” - Nis, Serbia and Montenegro
²Institute for Biology, University Medical School – Nis, Serbia and Montenegro

American Journal Of Reproductive Immunology, 2004;51(6) pp.:401-441.

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, “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 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

24^th 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.

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Misgav Ladach metoda Carskog reza

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S. Kojic¹, I. Bubanovic², V. Jeremic¹, G. Filipovic¹

 ¹Ginekolosko-akusersko odeljenje, Zdravstveni Centar Paracin, ²”Medika Centar”, Nis

REZIME

Carski rez predstavlja jednu od najcesce izvodjenih hirurskih intervencija. Iz ovih razloga postoji veliki interes za unapredjenjem i pojednostavljivanjem tehnike Carskog reza, kao i smanjenjem troskova izvodjenja same operacije. Misgav Ladach modifikacija Carskog reza predstavlja jednu od modifikacija koja omogucava izvesne prednosti u odnosu na standardnu tehniku, i to u smislu ustede savnog i anestezioloskog materijala, kraceg trajanja operacije, manju postoperativnu potrebu za analgeticima i antibioticima, kao i brze uspostavljanje crevne peristaltike. Iako su nasa iskustva u primeni Misgav Ladach modifikacije Carskog reza prikupljena na relativno maloj seriji pacijentkinja, ona potvrdjuju navode iz literature koja se odnose na prednosti ove modifikacije u odnosu na tradicionalnu tehniku.

Zbornik radova XLVIII Ginekolosko-akuserske nedelje SLD, Beograd. str.:139-143.

Diversification of Cytokines Across Vertebrate Immune System Evolution, Reproductive Efficacy and Tumor Escape

¹Ivan Bubanovic and ²Stevo Najman

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.

Download the Contents .pdf file of this Volume

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

12^th 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 and ²Stevo Najman

 ¹Ob/Gyn Department, Medica Centre, Nis, Serbia and Montenegro
²Institute for Biology, Medical School – Nis, Serbia and Montenegro

Paper N^o 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 patient’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 will be presented on the

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 Leucocyte Differentiation Antigens
34th Annual Scientific Meeting of the Australasian Society for Immunology

Autoimmunity and Alloimmunity – by Products of Adaptive Immunity and Sources of Anti-tumor Immunity Failure

¹Ivan Bubanovic and ²Stevo Najman

¹Department of Obstetrics and Gynecology – “Medica Center” - Nis, Serbia and Montenegro
²Institute for Biology, University Medical School – Nis, Serbia and Montenegro

American Journal Of Reproductive Immunology, 2004;51(6) pp.:401-441.

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 “self” 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 “latently” 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 – 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:

Impact of Biotechnology on Predictive Oncology & Intervention Strategies

Nice, France • February 7 - 10, 2004

and

24^th Annual Meeting of the American Society for Reproductive Immunology (ASRI)

St. Louis, Missouri, USA • June 3-6, 2004.

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

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

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 “long-term evolutionary relations” could represent “key factors” 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 – 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.