IMPLICATIONS TO IMMUNE THERAPY OF ACUTE

RADIATION SYNDROMES. PART 1.

DMITRI POPOV PHD, RADIOBIOLOGY (CANADA), MD( RUSSIA).

IMPLICATIONS TO IMMUNOTHERAPY OF ACUTE RADIATION SYNDROMES.

• TECHNICAL REPORT: IMPLICATIONS TO IMMUNE THERAPY OF ACUTE RADIATION SYNDROMES. PART 1.

• DMITRI POPOV• TECHNICAL REPORT · APR 2015• ADD RESOURCES• FILE NAME: IMMUNO-THERAPY OF ARS..PPTX

DOI: 10.13140/RG.2.2.26677.47845

ABBREVIATIONS

• ABBREVIATIONS: ANTIGEN-PRESENTING CELLS; ATAXIA TELANGIECTASIA MUTATED; CYTOTOXIC LYMPHOCYTES; DAMAGE-ASSOCIATED MOLECULAR PATTERNS ;DENDRITIC CELLS; HEAT SHOCK PROTEINS; INTRACELLULAR ADHESION MOLECULE; IL - INTERLEUKIN; MYELOID-DERIVED SUPPRESSOR CELLS; MAJOR HISTOCOMPATIBILITY COMPLEX; NATURAL KILLER; TOTAL-BODY IRRADIATION; TOLL-LIKE RECEPTOR; RADIATION, IMMUNOGENIC MODULATION, ANTIGEN-PROCESSING MACHINERY.

THE IMMUNE SYSTEM.

• THE IMMUNE SYSTEM CREATES A COMPLEX REGULATORY BALANCE, MAINTAINING IMMUNOLOGICAL COMPOSURE DESPITE POWERFUL PATHOPHYSIOLOGICAL STIMULI SUCH AS RADIATION.

• RADIATION INDUCE VARIOUS CELL DEATH MODALITIES VIA APOPTOSIS OR SPECIAL FORM OF NECROSIS, RELEASING SELF-CELL-DERIVED ANTIGENS AS WELL AS ACUTE PRO-INFLAMMATORY SIGNALS THAT COULD BE EXTREMELY IMPORTANT FOR BIOLOGICAL SEQUELAE AND TRIGGERING ANTI-RADIATION IMMUNE RESPONSE.

RADIATION AND IMMUNE SYSTEM.

• AFTER IRRADIATION MAMMALS DEMONSTRATED THE PRESENCE OF IMMUNE-SUPPRESSION. HOWEVER, EVEN MULTIPLY RADIATED MAMMAL DEMONSTRATED SPECIFIC IMMUNE RESPONSES.

• PATIENTS WITH SIGNIFICANT TUMOR BURDEN ARE CAPABLE OF GENERATING DE NOVO TUMOR- SPECIFIC IMMUNE-RESPONSES (LAHERUETAL.,2008).

ANTIGENIC COMPOSITION AFTER IRRADIATION.

• EXPERIMENTS ON GUINEA PIGS AND ALBINO RATS BY THE ANAPHYLAXIS WITH DESENSITIZATION METHOD SHOWED THAT SHF IRRADIATION GIVES RISE TO CHANGES IN THE ANTIGENIC COMPOSITION OF VARIOUS TISSUES (BRAIN, LIVER, KIDNEY, SPLEEN). THESE CHANGES ARE CHARACTERIZED BY THE APPEARANCE OF QUALITATIVELY NEW ANTIGENS AND THE DISAPPEARANCE OF SOME OF THE ANTIGENIC PROPERTIES OF THE NORMAL TISSUE. ANTIBODIES AGAINST IRRADIATED AND NORMAL BRAIN TISSUE WERE REVEALED BY THE COMPLEMENT FIXATION TEST IN THE COLD. BULLETIN OF EXPERIMENTAL BIOLOGY AND MEDICINE EFFECT OF SHF IRRADIATION ON TISSUE ANTIGENIC PROPERTIES AND AUTO-ALLERGIC PROCESSES

• AUGUST 1974, VOLUME 78, ISSUE 2, PP 916–919. G. I. VINOGRADOV• YU. D. DUMANSKII

ANTIGENIC COMPOSITION OF IRRADIATED TISSUES.

• CHANGES IN THE LEVEL OF OXIDATIVE DAMAGE TO PROTEINS IN CD1 OUTBRED MICE Γ IRRADIATED WITH A DOSE OF 3 GY HAVE BEEN STUDIED. THE CHANGES WERE ESTIMATED FROM THE AMOUNT OF CARBONYL GROUPS (CG) IN THE PROTEINS. IT WAS FOUND THAT TWO HOURS AFTER EXPOSURE TO Γ RADIATION, THE AMOUNT OF CG IN THE CYTOPLASMIC AND NUCLEAR FRACTIONS OF THE LIVER, HEART, BRAIN, AND SPLEEN SHARPLY INCREASED. TWO MONTHS AFTER IRRADIATION, THE LEVEL OF CG IN THE CYTOPLASMIC AND NUCLEAR SUBCELLULAR FRACTIONS OF THE LIVER AND BRAIN DECREASED TO THE LEVEL OF CG IN THE CONTROL ANIMALS, WHICH WERE NOT EXPOSED TO RADIATION.

• RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY. CHANGES IN THE ANTIGENIC PROPERTIES OF PROTEINS OF LABORATORY MICE DURING OXIDATIVE STRESS

JULY 2009, VOLUME 35, ISSUE 4, PP 469–473. E. A. RASSKAZOVA , V. B. SADOVNIKOV

ANTIGENIC PROPERTIES OF IRRADIATED TISSUES.

• IN THE SUBCELLULAR FRACTIONS OF THE HEART AND SPLEEN, THE INCREASE IN THE DEGREE OF DAMAGE WAS MORE SIGNIFICANT AND A HIGH LEVEL OF DAMAGE WAS OBSERVED EVEN TWO MONTHS AFTER IRRADIATION. AN ENHANCEMENT OF THE ANTIGENIC PROPERTIES OF PROTEINS FROM THE LIVER, HEART, AND SPLEEN IN THE POST-IRRADIATION PERIOD WAS FOUND. SPLEEN PROTEINS WERE MOST IMMUNOGENIC. A COMPARISON OF THE ANTIGENIC PROPERTIES OF PROTEINS ISOLATED FROM THE TISSUES 60 DAYS AFTER IRRADIATION REVEALED A CORRELATION BETWEEN THE LEVEL OF OXIDATIVE DAMAGE AND THE IMMUNOGENICITY OF THE TOTAL PROTEIN FRACTION.

• RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY. CHANGES IN THE ANTIGENIC PROPERTIES OF PROTEINS OF LABORATORY MICE DURING OXIDATIVE STRESS

JULY 2009, VOLUME 35, ISSUE 4, PP 469–473. E. A. RASSKAZOVA , V. B. SADOVNIKOV

ANTIGENIC PROPERTIES AND DAMAGE OF IRRADIATED TUMORS.

• RADIATION THERAPY (RT) IS USED FOR LOCAL TUMOR CONTROL THROUGH DIRECT KILLING OF TUMOR CELLS. RADIATION-INDUCED CELL DEATH CAN TRIGGER TUMOR ANTIGEN-SPECIFIC IMMUNE RESPONSES. RADIATION HAS BEEN DEMONSTRATED TO INDUCE IMMUNOGENIC MODULATION (IM) IN VARIOUS TUMOR TYPES BY ALTERING THE BIOLOGY OF SURVIVING CELLS TO RENDER THEM MORE SUSCEPTIBLE TO T CELL-MEDIATED KILLING. LITTLE IS KNOWN ABOUT THE MECHANISM(S) UNDERLYING IM ELICITED BY SUB-LETHAL RADIATION DOSING. RADIATION-INDUCED IMMUNOGENIC MODULATION OF TUMOR ENHANCES ANTIGEN PROCESSING AND CALRETICULIN EXPOSURE, RESULTING IN ENHANCED T-CELL KILLING. ONCOTARGET. 2014 JAN; 5(2): 403–416. SOFIA R. GAMEIRO,1 MOMODOU L. JAMMED,1 MAX M. WATTENBERG,1 KWONG Y. TSANG,1 SOLDANO FERRONE,2 AND JAMES W. HODGE1

• PUBLISHED ONLINE 2013 DEC 31. DOI:  10.18632/ONCOTARGET.1719

ANTIGENIC PROPERTIES OF IRRADIATED NORMAL TISSUES AND TUMOR TISSUES.

• AUTHORS HAVE EXAMINED THE MOLECULAR AND IMMUNOGENIC CONSEQUENCES OF RADIATION EXPOSURE IN BREAST, LUNG, AND PROSTATE HUMAN CARCINOMA CELLS. RADIATION INDUCED SECRETION OF ATP AND HMGB1 IN BOTH DYING AND SURVIVING TUMOR CELLS. IN VITRO AND IN VIVO TUMOR IRRADIATION INDUCED SIGNIFICANT UPREGULATION OF MULTIPLE COMPONENTS OF THE ANTIGEN-PROCESSING MACHINERY AND CALRETICULIN CELL-SURFACE EXPRESSION. AUGMENTED CTL LYSIS SPECIFIC FOR SEVERAL TUMOR-ASSOCIATED ANTIGENS WAS LARGELY DICTATED BY THE PRESENCE OF CALRETICULIN ON THE SURFACE OF TUMOR CELLS AND CONSTITUTED AN ADAPTIVE RESPONSE TO ENDOPLASMIC RETICULUM STRESS, MEDIATED BY ACTIVATION OF THE UNFOLDED PROTEIN RESPONSE. RADIATION-INDUCED IMMUNOGENIC MODULATION OF TUMOR ENHANCES ANTIGEN PROCESSING AND CALRETICULIN EXPOSURE, RESULTING IN ENHANCED T-CELL KILLING. ONCOTARGET. 2014 JAN; 5(2): 403–416. SOFIA R. GAMEIRO ET AL.

ANTIGENIC PROPERTIES OF IRRADIATED NORMAL AND IRRADIATED TUMOR CELLS.

• THIS STUDY PROVIDES EVIDENCE THAT RADIATION INDUCES A CONTINUUM OF IMMUNOGENIC ALTERATIONS IN TUMOR BIOLOGY, FROM IMMUNOGENIC MODULATION TO IMMUNOGENIC CELL DEATH. AUTHORS ALSO EXPAND THE CONCEPT OF IMMUNOGENIC MODULATION, WHERE SURVIVING TUMOR CELLS RECOVERING FROM RADIATION-INDUCED ENDOPLASMIC RETICULUM STRESS BECOME MORE SENSITIVE TO CTL KILLING. THESE OBSERVATIONS OFFER A RATIONALE FOR THE COMBINED USE OF RADIATION WITH IMMUNOTHERAPY, INCLUDING FOR PATIENTS FAILING RT ALONE. . RADIATION-INDUCED IMMUNOGENIC MODULATION OF TUMOR ENHANCES ANTIGEN PROCESSING AND CALRETICULIN EXPOSURE, RESULTING IN ENHANCED T-CELL KILLING. ONCOTARGET. 2014 JAN; 5(2): 403–416. SOFIA R. GAMEIRO ET AL. HTTPS://WWW.NCBI.NLM.NIH.GOV/PMC/ARTICLES/PMC3964216/

ANTIGENIC PROPERTIES OF IRRADIATED TISSUES.

• STUDY WAS CARRIED OUT TO EVALUATE THE APPLICATION OF FOOD IRRADIATION TECHNOLOGY AS A METHOD FOR REDUCING MILK ALLERGIES. BOVINE ALPHA-CASEIN (ACA) AND BETA-LACTOGLOBULIN (BLG) WERE USED AS MILK PROTEINS. USING MILK-HYPERSENSITIVE PATIENTS' IMMUNOGLOBULIN E (IGE) AND RABBIT IGGS INDIVIDUALLY PRODUCED TO ACA AND BLG, THE CHANGES OF ALLERGENICITY AND ANTIGENICITY OF IRRADIATED PROTEINS WERE OBSERVED BY COMPETITIVE INDIRECT ENZYME-LINKED IMMUNOSORBENT ASSAY. ALLERGENICITY AND ANTIGENICITY OF THE IRRADIATED PROTEINS WERE CHANGED WITH DIFFERENT SLOPES OF THE INHIBITION CURVES. THE DISAPPEARANCE OF THE BAND ON SODIUM DODECYL SULFATE-POLYACRYLAMIDE GEL ELECTROPHORESIS AND INCREASE OF THE TURBIDITY SHOWED THAT SOLUBILITY OF THE PROTEINS DECREASED BY RADIATION, AND THIS DECREASE MIGHT BE CAUSED BY AGGLOMERATION OF THE PROTEINS. THESE RESULTS INDICATED THAT EPITOPES ON MILK ALLERGENS WERE STRUCTURALLY ALTERED BY GAMMA IRRADIATION. J FOOD PROT. 2001 FEB;64(2):272-6.

• EFFECTS OF GAMMA RADIATION ON THE ALLERGENIC AND ANTIGENIC PROPERTIES OF MILK PROTEINS.• LEE JW1, KIM JH, YOOK HS, KANG KO, LEE SY, HWANG HJ, BYUN MW.

ANTIGENIC PROPERTIES OF IRRADIATED TISSUES.

•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

• J FOOD PROT. 2000 JUL;63(7):940-4.• EFFECTS OF GAMMA RADIATION ON THE CONFORMATIONAL AND ANTIGENIC PROPERTIES OF A HEAT-STABLE MAJOR

ALLERGEN IN BROWN SHRIMP.• BYUN MW1, KIM JH, LEE JW, PARK JW, HONG CS, KANG IJ.

ANTIGENIC PROPERTIES OF IRRADIATED TISSUES.

• STUDIED WAS THE EFFECT OF GAMMA-RAYS AT RATES OF 1 TO 20 MR ON THE TOXIC, ANTIGENIC, AND IMMUNOGENIC PROPERTIES OF THE O-ANTIGEN EXTRACTED FROM SALMONELLA GALLINARUM-PULLORUM BY THE METHOD OF BOIVIN. IT WAS FOUND THAT THE IRRADIATION OF AQUEOUS SOLUTIONS OF THE O-ANTIGEN LOWERED THE TOXIC, ANTIGENIC, AND IMMUNOGENIC CAPACITY WITH THE INCREASE IN THE DOSE OF TREATMENT. STRONGEST DETOXICATION OF THE ENDOTOXIN WAS PRODUCED THROUGH IRRADIATION AT THE RATE OF 10 MR, AND ESPECIALLY AT 20 MR. THE ANTIGENIC ACTIVITY, ESTABLISHED THROUGH THE HYPERIMMUNIZATION OF RABBITS WAS EXPRESSED BEST AT IRRADIATION RATES OF 1 AND 5 MR. AT SUCH TREATMENTS THE IMMUNOGENIC CAPACITY REMAINED INTACT AS FOLLOWED UP BY THE MURINE PROTECTION TEST. VET MED NAUKI. 1977;14(6):53-60.

• [CHANGES IN THE TOXIC, ANTIGENIC AND IMMUNOGENIC PROPERTIES OF THE O-ANTIGEN OF SALMONELLA GALLINARUM-PULLORUM IRRADIATED WITH GAMMA RAYS].

• [ARTICLE IN BULGARIAN]• STEFANOV V, LOZEVA T, STEFANOVA M, BALIMEZOV I.

TOXICITY OF IRRADIATED TISSUES.

• ALTHOUGH THE FUNCTIONAL AND STRUCTURAL TOLERANCE OF NORMAL TISSUE TO RADIOTHERAPY IS CONTEXTUAL , STUDIES OF CELL AND TISSUE RESPONSE TO IONIZING RADIATION HAVE LED TO AN IMPROVED UNDERSTANDING OF THE PATHOGENESIS OF RADIATION TOXICITY.

•  BENTZEN SM. PREVENTING OR REDUCING LATE SIDE EFFECTS OF RADIATION THERAPY: RADIOBIOLOGY MEETS MOLECULAR PATHOLOGY. NATURE REV. CANCER. 2006;6:702–713. [PUBMED]

TOXICITY OF IRRADIATED TISSUES.

• A KEY CHALLENGE IN RADIOTHERAPY IS TO MAXIMIZE RADIATION DOSES TO CANCER CELLS WHILE MINIMIZING DAMAGE TO SURROUNDING HEALTHY TISSUE. AS SEVERE TOXICITY IN A MINORITY OF PATIENTS LIMITS THE DOSES THAT CAN BE SAFELY GIVEN TO THE MAJORITY, THERE IS INTEREST IN DEVELOPING A TEST TO MEASURE AN INDIVIDUAL’S RADIOSENSITIVITY BEFORE TREATMENT. VARIATION IN SENSITIVITY TO RADIATION IS AN INHERITED GENETIC TRAIT AND RECENT PROGRESS IN GENOTYPING RAISES THE POSSIBILITY OF GENOME-WIDE STUDIES TO CHARACTERIZE GENETIC PROFILES THAT PREDICT PATIENT RESPONSE TO RADIOTHERAPY. NAT REV CANCER. 2009 FEB; 9(2): 134–142.

• PUBLISHED ONLINE 2009 JAN 16. DOI:  10.1038/NRC2587• NORMAL TISSUE REACTIONS TO RADIOTHERAPY• TOWARDS TAILORING TREATMENT DOSE BY GENOTYPE• GILLIAN C. BARNETT, CATHERINE M. L. WEST, ALISON M. DUNNING, REBECCA M. ELLIOTT, CHARLOTTE E. COLES, 

PAUL D. P. PHAROAH, AND NEIL G. BURNET

TOXICITY OF IRRADIATED TISSUES.

• THE EXTENT OF STRUCTURAL DAMAGE TO A TISSUE GENERALLY DEPENDS ON CELL RADIO-SENSITIVITY. THE RELATIONSHIP BETWEEN ANATOMICAL AND STRUCTURAL RADIATION DAMAGE AND FAILURE OF ORGAN FUNCTION IS DIFFERENT FOR DIFFERENT ORGANS, AND DEPENDS MORE ON ORGAN PHYSIOLOGY THAN ON CELL SURVIVAL.

• NAT REV CANCER. 2009 FEB; 9(2): 134–142.• PUBLISHED ONLINE 2009 JAN 16. DOI:  10.1038/NRC2587• NORMAL TISSUE REACTIONS TO RADIOTHERAPY• TOWARDS TAILORING TREATMENT DOSE BY GENOTYPE• GILLIAN C. BARNETT, CATHERINE M. L. WEST, ALISON M. DUNNING, REBECCA M. ELLIOTT, 

CHARLOTTE E. COLES, PAUL D. P. PHAROAH, AND NEIL G. BURNET

RADIATION TOXICITY.

• HTTP://WWW.NATURE.COM/NRC/JOURNAL/V15/N7/FIG_TAB/NRC3958_F2.HTML• FROM THE

TUMOUR MICROENVIRONMENT AFTER RADIOTHERAPY: MECHANISMS OF RESISTANCE AND RECURRENCE

• HOLLY E. BARKER, ET AL.• SLIDE NUMBER 18 NEXT

RADIATION TOXICITY

RADIATION INDUCED NECROSIS VS APOPTOSIS.

• HTTP://WWW.SLIDESHARE.NET/DLPOPOV/RADIATION-TOXICITY-NECROSIS-APOPTOSIS

RADIATION TOXICITY

• 1. IRRADIATION GIVES RISE TO CHANGES IN THE ANTIGENIC COMPOSITION OF VARIOUS TISSUES (BRAIN, LIVER, KIDNEY, SPLEEN). THESE CHANGES ARE CHARACTERIZED BY THE APPEARANCE OF QUALITATIVELY NEW ANTIGENS AND THE DISAPPEARANCE OF SOME OF THE ANTIGENIC PROPERTIES OF THE NORMAL TISSUE.

• TOXICITY DEPEND ON MITOTIC RATE AND METABOLIC RATE OF IRRADIATED CELLS.• LESS OR LOW OR ABSENT MITOTIC RATE AND METABOLIC RATE OF IRRADIATED CELLS OR

PROTEINS COULD REDUCE TOXICITY, ANTIGENICITY, ALLERGENICITY.• HIGH METABOLIC AND MITOTIC RATE OF CELL WHICH UNDERWENT TO RADIATION COULD

MAKE TOXICITY HIGHER, ANTIGENICITY AND ALLERGENICITY OF IRRADIATED CELL HIGHER.