Cell Medicated Immunological Defects in Man After Irradiation

Page 1

' PU ULI C HEALTH SER VIC li NATIONAL INSTITUTES 01' HEALTH - IT LE OF PROJECT ' CELL MEDICATED IMMUNOLOGICAL DEFECTS JN MAN AFTER IN RADIATION PRINCIPAL INVESTIGATOR ASSOCIATES AND DEPARTMENT I SPECIALTY P HOY KG OHM ED IC INE RECIPIENT IN bT IT UTI ON PERIOD FOR THIS N RPI SUMMARY OF PROJECT The primary objective of this pro posa1.i ~the study of lymphocyte populations in the per ln her al blood of Der sons given X - ray treatments to the thymus gland during infancy and of Persons irradiated prenatal ly as a result of pel vi met rlc studies, If abnormalities of theT - 1Yr np ho cyte s j can be demonstrated as has been reported in women treated with x - rays ' Post - oDer at iv ely for breast cancer, this might be a factor in explaining the excessive numbers of neor ; la sms in these two po uul at lons,Subjects irradiated in infancy Will be chosen from the large PopUlatiOn in Rochester given x - ray treatments to the thymus gland and followed by epidemiological survey for the past20years, The secondary objectives of the program are the study of the thymus horn on as(thy mos in and thy most at in)in those people whose thymus glands were irradiated in infancy and the study of chromosome abnormalities by the chromosome banding technique collaboration of Dr. Con a ld Peterson at The Los Alamos Scientific Laboratory.

Page 2

NOTICE OF RESEARCH PROJECT ' I SUPPORTING AGENCY AGENCY S NUMBER IS, BUh EAU OF HAD IO LUG ICAL HEALTH NEOPLASMS IN IRRADIATED HU MAh POPULATIONS TITLE OF PROJECT PRINCIPAL INVESTIGATOR ASSOCIATES AND DEPARTMENT SPECIALTY ROCH & STER, NEW YOHK 14620 SU Y MARY OF PROJECT he propose to continue to survey three human peculations with known radiation exposures to ascertain the quantitative risks to health of such exposures.The populations are composed of (1) persons given Xray treatment to the thymus gland in infancy and non - irradiated sib lin q ns and age - specific general population of upstate New York a s therapy to then as op nary nx in childhood and sibling and general population controls,this study was begun in 1961; and(3) women given x - ray treatments to the breast for acute postpartum mast it is j in addition to the general ro pul ation,this study,be sun in1962,Will be controlled by survey of a comparable group of woven in New York City with the same rne a ical cond it lon not treated by X - rays. In aaa it ion to the epidemiological study of these populations conducted by mailand telephone survey,ue plan to continue an examination program of selected thymus - lr radiated oersons in a subgroup with a high risk of a eve loping thyroid neoplasms,Particular attention is given to treatment of radiation - induced goiter with suppress ive hormone therapy,Because of the recent evidence for immunological Q Placed on diseases of this type.

Page 3

The aim ot this project is to explain the mechanism(s1of organism el recovery fro1radiation injury in terms of stem cell re population and d if tere nti ation,which are studied in the animal,and cellular rpc over yann repair of sub lethal damaqe, which are studied in culture. l'he abl lit y to repair,and possibly the induction Of sub - let nal damage have been sho v n to be limited to specific times inthe cell cycle.Ultra cent rl tug arion methods and specific inhibitors of DNA # RNA,and protein syn t nes is are being used to determine the molecular in ech an iso(SIo t repair In mammalian cells(HeLa).The plan arian is a usetirl analog for In a jr a alian cell systems such as bone marrow, liver, skin,dyne ter ~ rnin nr J lan arians urs viva l curves and stem cell counts after rinse traction atl on,shielding,an a stimulation of d it fe rent i ation, the nature ot th p control system(s)w n ich govern(s)reF o Pul ation is i iesu lts : Asemi - automated gradient, analysis system has been des lyne d and built e erm lt t lng large numbers of gradients to be procc ~ sseu.Pe ut ral sUCcrse gradients have been used to demonstrate the $z 1n ciUC tl Ort by ionizing Ka : ii ation and the subsequent repair of double a strand break ' s in the D Nr \ of L51784 mouse leuk emi c cells. Low dose cell c3 cycle stage specific flrllu to xi cities and the acquisition of " immunity ff J=: t o sucIi Cox ic effects hq ve been found tor some commonly used metabolic

Page 4

techniques.Unfortunately, developmental techniques can be very time consuming and may be unrewarding. I would prefer to see her spend more time on the first two projects which as I indicate dJ are already ongoingJ and will be in th immediate future extremely fruitful and informative. I n my opinion, Dr. Lange has made some very sighi fi cant improvements in the technique of sucrose gradient for the analysis of damaged DNA. Furthermore, he intends to and is already doing analysis of double-strand breaks in neutral sucrose and their relationship to the recovery from sub lethal or so - called El kind damage i n mammalian cells. There are many programs going on at this ' time in this area of sub lethal damage i n DNA strand breaks. However, this proposal and this program of Dr. Lange's i s one which I think is of superior quality and should be funded. Dr. Lawrence appears to be a very knowledgeable person who has drive, &/de recognizes the great value of Sherman's cytochrome system in yeast and be intends to use this to study the genetics and biochemistry of repair in the eu cary ote yeast.I think at this point it is appropriate to mention that having heard all these different projects in yeast and in particular / the elegant system developed by Dr. Sherman, that this Institution here has got to have certainly what I would reckon the most powerful genetics, microbiology,biochemistry unit for the study of yeast that there is a n + lace in the world. .3tjedohgrou$have the research tools of this marvelous cytochrome system and the different approaches that people

Page 5

biochemical geneticists. The importance of his work i s illustrated by his recent discovery erg i s an established, active contributor, one o f a dwindling number of phagef leading to a technological advance in analysis of DNA replication complexes, and also yielding a genetic approach to translational control. His contributions in terms of his ready sharing o f these new tools with the maior labs best suited to exploit them should not be overlooked. Such programs offer a source o f molecular biology information of basic importance. They also offer a rapid, inexpensive discipline for teach*7 W L Lorkers with not suitable for graduate students should post-doctoral support be awilable. Dr. Wi#berg could extend his contribution other phage problems It would be a good hvestment. Recommendation: continue at least at current level.- 5hristopher Lange, project 254-fF;e cellular and molecular basis o f recovery Dr. Lange i s a biophysist whose biological theories and assumptions my expertise. His very practical studies of molecular weight determination o f DNA, however, are of immediate importance both in general and in relation to other AEP's in this department. Such contributions and interactions with members o f this group are a major asset to the overall program. Recommendation: continue present support. Dr. Morton W. Miller, project 2512 k di ation cytology, chromosome abberations direction. Drs. Miller and Carstensen have developed a convenient system for examining cellular and nuclear m s of two MHz ultra3und This has been a productive program which has recently taken on a more significant 4pk-G- in the doses used in human diagnosis and therapy. Their results are indicative o f adverse defects. They have a number of important questions o f non-thermal possibly cavitation .effects to be pursued in Vicia fabo and in mammalicy systems. Their approach should be successful. Recommendation: continue project at least at current levels. This program should not be lost for lack of c l e a r guidelines of agency support.