jim q/r1 - sf. ballale ~ prgusn roped bg oben > Zo Aveeatl 40 rb op pys ro byrricnatt pn pO NITE poet g fy Morel a p pes wrtwed poten wacboo am defpaal arent }9 nN? Borman, ME 1470? The anttarl, cadre nt dangle lle. jdm. PHx . 1): 543 - 547 po bbo LH, bineinfored, Mella Abt ft [pried rodea.— pr ch typruco. — third ure e Ley Artuge mlb Foie wee 2.) x /o 03 M dh the stechdl: Lied at js edt , wi tr vwkircce 4, The, HO cl was |. 25 - —-75 xX/b ed at bhav ceanrres TE et anion ole ell 8 Ar i> Metalic MEE : Nyphint alain Ar tis 18 3 Aner. WN, Wa to ler, = Bu AGE to’ “9: wy IO MG hc Md t Conbote 4577 a wit eh il wy pare Lurnetl (1h PAS 196 bb: /- apd Canenon Teale Care + begeene rn t/r0 huts ltd. a rary fist as ff Meloanee fe, deafaed ln spel batialed with W5A remme saresTerces Clad / fd pli f id opi joo ti ie ae 937 Uadlipe coated flee ug. ae pan See elo ee Lupher 4 rman, I] PWAS 37:57 5 Qotiber Bese, MYAS SI: /773. uf “hy mental Treatment of Total-body trradiation Injury: A Brief Revi ew. Blood, J. Hem. J2: Th6-753. In general after 900 r of x-rays one to ten million nucleated bone marrow cells give optimal thirty day survival. However, as few as 50,000 cells will allow a small percentage of mice to survive. (Urso, P., and Congdon, C.C. 1957 The effect of the amount of isologous bone marrow injected on the recovery of hematopoietic organs, survival, and body weight after lethal irradiation injury in mice. Blood 12:251.) "The effective cell type, or types, in the administered bbood-forming tissue has not been clearly determined. Since dividing cells are necessary, the stem cells and reticulum cells of the hematopoietic tissues are implicated.'' IV route best, interparitoneal effective,intramuscular and subcutaneous ineffective in mice. Bone marrow implant may be delayed three to four days. Billen, D. 1957 Recovery of lethally irradiated mice by treatment with bone marrow cells maintained in vitro. Nature 179:574.- indicated bone marrow cells maintained incculture were affective after 21 days. 7? are these proliferating in cul ture? Reviews evidence that the peripheral blood elements are of the donor typegq in theserescued animals. Maxwell, R. E. and Weston, J. K. 1956 (Abstract). Amelioration of Myleran- induced bone marrow damage in rats with homologous marrow injections. Fed. Proc. 15:457. Chemical injury to bone marrow can also be reversed by implantation. Secondary reactions noted with bone marrow of homologous origin. Congdon believes this is a reaction of the host to the foreign marrow. This paper does not discuss the use of other tissues from the donor although it is evident that spleen will also work. Kerwin, RM. and C.C. genaden : (1957 Repepuletion ef Hemate- peletic Tissues and Bleed in Je of the Nat. Cancer last. Lethal ly X-irradiated Mice by “193 Homeloesus Bane-Merrew fatle. = = 575-88. Reviews other evidence that bone marrow repopulated the marrow, produced rbc, and under some conditions repopulated the thymus and lymph nodes of the irradiated host. They used the sensitization to homografts as a test of the persistence of donor cells. They conclude themselves that there is extensive repopulation. Schwartz, E. £., A.C. Upten, and C.C. on ea 1957 A Fa- Prec. of Sec. for Exp. Biel. ‘tal Reaction Caused by tmp) an- and Ned. 96:797T-800. | tation ef Adult Parental Spleen Tissue in Irradiated F) Mice. Fatal reaction caused by implantation of adult parental spleen tissue and so on. This is a rest of the runt disease reaction where parental transplants into hybrid irradiated recipients resulted in runt dieease. In this investi- gation bone marrow rarely and infrequently, 11 out of 59, gave the runt disease whereas spleen cells gave extensive and prompt mortality. The bone marrow from presensitized donors was more regularly mortal. Other investigators have had higher incidences of runt disease with bone marrow and this may depend on the Strain. The disease was not found when isologous hybrid spleen cells were used, and therefore there is apparantly competent replacement by such cells. The dose of parent spleen cells was correlated with the time of death of the recipient. Few recipients of less than 75,000,000 spleen cells died in the first thirty days, many others succombed in the second month. Whereas larger doses of bone marrow gave less consistent survival. There is nothing here on homograft receptivity of these gyimeras. Congden, C.C. and 1.5. Urse 195:'7 Hemelegeus Bene Karrew In tajury in ies. de Path w... A discussion of the homologous bone marrow disease which they are unsure whether This may not be the same as this develops from host versus graft or visa versa. It may reflect the total absenee of the lymphocytic homologous spleen disease. system. A few animals did survive for prolonged periods. MG pele 6863s fhpeatit Lirasecy pyle) all webct anna, Mrgpene WS 07 feces of arertied cpocter bus Mla o inler Myrmnd UY BaP uty nr, 6 copper EES we why, fff. hfe. /4 95 peat 90;.5 3 | See hacle dpe andl Freed (p21 1) fney means MST pn, Bixnen, F.J. and P.H. Maurer, 1955 tmnunelegic Unrespens! ve- ness induced by Pretein Anti- gens; J. Exp. Med. 101 :245- 257. Most adult rabbits could not be made lastingly unresponsive and the effect there is undoubtedly due to growth excess of the antigen, heterologous plasma proteins. However, in rabbits infused from the time of birth the induced unresponsiveness lasted throughout the period of observation, ten to eleven months, long after disappearance of all detectable foreign protein in the serum. These were: looked for by capillary precipitin ring tests. All rabbits retained their confidence to unrelated protein antigens. Unresponsiveness was not trans~- mitted to the offspring. Antibodies were also being formed against contaminating components of the innocula and therefore large doses are needed to induce unres- ponsiveness. ‘Assuming the usual half lives of foreign serum protein non-immune rabbits only a small fraction of a microgram of the infused proteins would be expected in the entire rabbit four to six months after the infusions. '' Whenever the immunologic mechanisms become operative the foreign material is present in considerable quantity and it may be difficult for the rabbit to treat this material as an antigen. In such a situation it is even possible that the foreign protein might be accepted as non-antigenic along with the host's own constituents.'' p. 255. ' No direct measurements for the last traces of foreign protein in the tissues are feasible." Passively introduced antibody was not more rapidly eliminated, also tending to rule out the presence of significant amounts of the antigenic proteins. This anitbody was recorded as having a normal half life. Nothing was determined however as to whether this passive antibody could accelerate the return of tesponsiveness and this is an important experiment to consider. Apparently Dixon doées not believe that persistence of the antigen is obligatory for unresponsiveness but his observations are inconclusive. Find references to the British work on the persistence of such antigens. Dixon, F.J. and Paul Meurer, 1955 Specificity ef the Se condary Respense te Protein Antigens. Tesht&-a31. When Bsa was followed by HSA a secondary response was found which included excess anti-BSA including BSA not reacting with HSA. On p. 429 several possible explanations are enumerated. 1. Some identical shared determinents present more often in BSA but not so readily detected in a absorption experiments on account of the rarity of the sites. However this should expect to participate in co-precipitation. 2. Storage of pre-formed antibody for which there is no precedent. 3. Inhibition of degredation of anti-BSA, again no precedent. 4, ' Some mechanism for production of antibody to the original antigen is stimulated by the subsequent administration of a relatéd antigen as more techniques are being developed by establishing the homogeneity of a protein. It is becoming apparent that there is no absolutely homogeneous protein... purified albumins may have as many as six components... however “production of the entire spectrum of antibodies to the original antigen is stimulated by the second antigen bearing only a limited antigenic similarity to the original antigen. Antibodies oriented only to the determinents peculiar to the first antigen also increase. Therefore the second antigen could not be acting merely as a template but rather would be stimulating a pre-existing mechanism oriented toward all the immunological characteristics of the first antigen. This has serious implications for the question of the: range of antibodies that can be produced by the individual responding unit, to the cell. This point has to be tested more directly. The possibility cannot be excluded that there will be stimulative reactions by antigen for antibody containing cells that are not reflected in: the precipitation test between antigen and antibody. But if this is the case one should detect a wider spectrum of response to the original antigen. This point has been studied in a paper by Maurer in the NM of Feb. 1944, Dixon did not try mixed primary with unrelated antigen. If the second antigen was unrelated to the first, for example, BGG, HSA, there was no effect. The effects seen were not large, the increases being of one order of magnitude only. Reberts, J.C. and F.J. Dixen, 1955 The Transfer of Lymph Nede Cells in the Study ef the immune Respense te Fore! gn Preteins. J. Exp. Med. 102: S19 392. Primary stimulated lymph node cells from rabbits transferred to X-rayed recipients and then given secondary stimulus. The amount of antibody synthesized by the individual innoculated cells was then calculated. They make the following assumed values: 1. Four billion lymphocytes equal 1 gram. 2. 350,000,000 molecules of rabbit antibody equal 0.1! micro-microgram of protein. They calculate that each transferred lymphoid cell makes one-third of its weight of antibody during the next five days. This is considered to be a minimum estimate since not all cells can be maximally active. This level of activity is considered to be cmmparable to that of the entire lymphoid population of the secondary rabbit. He assumes that 20-40 billion lymphoid cells per k}lo body weight are available in the rabbit for the immune response, and he used two kilo rabbits. For these estimates - Osgood, E.£., BLOOD, 1954, 9, 1141. Tivey, H. Li, J. G., and Osgood, E.E£. BLOOD, 1951, 6, 1013. date? : 5-10 yom [ba Lapageboardi abl — Bo md gfdrlin pot > lyn OG. freer ate Yekuys Toph aan set Phan WE goto hs seb mame Halden. [ull Pea Ee in Sine aed Dixon, F.J., and W.0. Weigle 1957 Antibody Production by Cells of the Neonatal Rabbit. Fed. Proc. 16:411. "The inability of the neonatal rabbit to make antibody is well recognized. Recently it has been observed that adult rabbit lymphoid cells capable of antibody synthesis after their transfer to X-irradiated adult rabbits do not make antibody after their transfer to neonatal recipients. This suggests that it is the internal environment of the neonatal rabbit and not necessarily the Tack of cells potentially capable of antibody production that is responsible for its immunological inadequacy. To test this possibility spenic and thymic cells of neonatal rabbits were exposed to shigella toxin in vitro, washed and transferred to neonatal and X-irradiated adult recipients. No significant agglutinin responses were observed in 14 neonatal recipients of live exposed cells or in 6 adult, X-irradiated recipients of heat killed exposed cells. However, in 9 of 20 adult X-irradiated recipients of live, exposed neonatal cells, significant agglutinin titers developed. This would suggest that lymphoid cells of the aeonatal rabbit can, under certain conditions, make an antibody response. Attempts were also made to alter the internal environment of the neonatal rabbit by injecting into them normal adult lymphoid cells prior to the transfer of adult lymphoid cells sensitized to Shigella toxin. Significant antibody responses were observed in 16 or 38 neonatal recipients pretreated with normal lymphoid cells and prior to the injection of sensitized lymphoid cells and O of 23 neonatal recipients injected with sensitized lymphoid cells only. {it appears from these data that injection of the normal adult lymphoid cells can make neonatal rabbits adequate recipients of antibody producing cells.'! Dixon, F.J. and W.0. Wel gle, 1957 The Nature ef the immune legic inadequacy ef Neonatal Rabbits as Revealed by Cell Transfer Studies. JEM. : These are rabbit lymph node cells which were capable of primary response to BSA and BGG as well as Shigella extract. These cells do not produce antibody in newborn recipients. However cells transferred during active ABF do continue to produce antibody. DQ xon Fede William Welgle, and J.C. Reberts, 1957 Cemparisen ef Asitibedy Respenses Asseciated with the Transfer ef Exudate, and Thymus Cells. J. lmmungt. 78:56-62. Peritoneal exudates as well as lymph nodes from pre-sensitized rabbits transferred sizable secondary antibody responses to x-rayed recipients. Thymic cells transferred much smaller responses. He concludes that either macrophages or lymphocytes can mature presamably into plasma cells in order to make antibody. The exudate cells were as effective as lymph node cells. See reference 6 for other previous work on thymus. ‘It would be interesting to know whether preparatory injections of antigen directly into or near the thymuses of our donors would have resulted in better transferring of antibody synthesis." Contra these experiments- Roberts, K.B. Brit. J. Exper. Path., 36:199, 1955, did not transfer a response to bacterial antigens but it is impossible to take these two papers side by side. ts..: Neil, A.L. and Fide Dixon. 1958 inmunehi stechenical Detection of Antibedy in. Cel! Transfer Studies. Avety Path Used preimmunized rabbits, to BSA, and lymph nodes. The suspensions contained 90 per cent lymphocytes, 8 per cent macrophages, and 2 per cent plasma cells. Flaorescent antibody technique was used to identify the introduced cells contining antigen and to follow their morphological tran$formation. Dixon concludes that in the primary response there is a transformation from lymphocytes into plams cells. By the fifth day most of the antibody-containing cells were of mature plasms cells. There was no great amount of mitotic activity but these animal had been intensively stimulated beforehand. ''Considering the minimal mitotic activity in the transfer sites it would appear that during their antibody response the transferred | ympho- wt cytes metamorphosed to the plasma.cells without division via the stages described. Egdahl, R.H. 1958 Immunological Maturation and Defects in Immunological Capacity Int. Arch. Allergy 12:305-321. The first part of this review refers to the development of antigenic specificity "'Brephoplastic transplantation applies to situations when the donor js fetal Or new-born.'' There is at least one claim that embryonic parathyroid could be successfully implanted into adolescent patients. (7)(6) He then refers to studies on acquired tolerance an additional reference being (8). Smith (13) 8 period embraces that time span when the animal response to the innoculation of foreign tissue with neither tolerance nor heightened resistance.'! Different species mature at different rates with respect to skin rejection. For example, fetal sheep at 100 days reject skin homografts (Schinkel; P.G. and Ferguson, K.A. 1953 Skin transplantation in the foetal lamb, Aust. J. Exp. Biol. Med. Sci. 6% 533-546) and ditto newborn calves. He remarks that newborn sheep lack gamma globulin but nevertheless reject the skin. However, it is not apparent that gamma globulin was absent throughout the entire period of the homograft response. There is a useful discussion on the maturation of gamma globulin in human children. Despite a high level of globulin, presumably of maternal origin, ‘'the newborn infant is incapable of responding with the usual antibody production during the first few weeks of life." Osborn, J.J., Dancis, J. and Julia, J.F. 1952 Studies on the immunology of the newboen infant, I. Age and antibody production, Pediatrics 9: 736. Then a review of Good's material, for example a child born from a globulin- negative mother. The child was born without globulin and remained so for six weeks of life. No antibody response was observed in the baby during the first two months. ''Between two and four months coincident with the first appearance of gamma globulin in the infant serum there appeared agglutinins against the H, 0, and B antigens, diptheria antitoxin and the child became shick negative at four months. Paper electrophoresis demonstrated a steady increase in gamma globulin concentration from 60 days onward, until at 10 months of age the pattern was apparently normal.!! Discussion of the immunological immaturity of the newborn. Refers first to Dixon and Weigle but he mentions (p. 313) "They found that the transfer of normal adult lymphocytes prior to transfer of sensitized lymphoid cells into neonates led antibody production by the transferred cells.'' Does Gus know about this? Dixon, F.J. and Weigle, W.0. 1957 Antibody production by cells of the neonatal rabbit, Fed. Proc. 16: 411. The experiments by Sterzl who claimed that subcellular particles from immunized rabbits would transfer abf to 5 day old rabbits, believing that this was due to the mi tocndria. EgdahY then refers to various theories of antibody formation. He then turns to hereditary defects in antibody formation giving a history of agammaglobulinemia. The leukocytes of these children are capable of transferring passive hypersensitivity to dinitrofluorobenzene. Skin homografts have succeeded to globulin negative recipients. Giedion, V.A. und Scheidegger, J. J. 1957 Kongenitale Immunparese bei Fehlen spezi fischer -Globuline und quantitativ normalem Gatwha-Globulin, Helvet, paed. Acta 12:241-259., #s~a case of specific lack of certain globulin components with homograft receptivity. 2 + Egdahl Good transferred homologous lymph node tissue subcutaneously to a globulin negative patient. Continued anti-samlonella antibody was demonstrated for a period up to two months but then disappeared. Author is concerned about possibility of runt disease. Gengozian, N., §.S. Urse, C.C. marrow, Proc. ef Soc. for Exp. Congdon, A.D. Conger, and T. Biel. and Hed. 96:714-720. Makinedan 1957 Thymus Speci- - ficity In Lethally trradiated | Mice Treated with Rat Bone These are x-rayed mice given rat bone marrow. The thymuses were tested by in vitro agglutination with anti-mouse and anti-rat serum. As reported elsewhere there is considerable stimulation of recovery of thymus by the heterologous bone marrow. "Agglutination tests (p. 718) indicate a repopulation of the thymus by rat type cells in lethally irradiated mice treated with rat bone marrow. The agglutination tests showed that repopulation by rat cells was 50 per cent complete on about the 2Ilst day after treatment and by 30 days all the cells in the thymus appeared to be of the rat type.'' This was confirmed by cytolo- gical examination. This result is in contrast to Kaplan's claim where parental bone marrow promoted regeneration of irradiated post-thymus by trans- plantation tests. Authors refer to experiments by Wolf and Upton where there was a small percentage of takes of regenerated thymus in the parent host. The question is left upon as to the cellular origin of the thymus cells including the general hypothesis of a multipotent cell. Germuth, F.G. 1956 The Role of Adrenocortical Steroids in Infection, Immunity, and Hypersensitivity, Pharmacological Reviews 8:1-24. Ascribes major role to the effect of cortisone on ''vascular tone''. For example resistence to formation to petechia. Cortison in Ebert's experiments reduced local reaction of rabbit gar to TB infection. This attbibuted to direct improvement of vascular response. Argues against much direct effect on leukocytes. Survey on these is confusing but concludes that there is no immediate effect on function. Halpin (Benacerraf, B., Halpern, B.N., Biozzi, G. and Benos. S.A. 1954 Quantitative study of the granulopectic activity of the reticulo-endothelial system l1t: The effect of cortisone and nitrogen mustard on the regenerative capacity of the R.E.S. after saturation with carbon. Brit. J. Exper. Path. 35:97-106.) found that there was no émmidiate effect on the uptake of carban partiples by the RE system but that continued capacity to take up carban was inhibited by cortisone. This was attributed to the inhibition of the multiplication of the RE cells. Cortisone inhibits wound healing and repair, again possibly secondary to vascular function. Conflicting evidence on the lysis of lymphocytes. Affirmative - Chase, J.H. White, A. add Dougherty, T.F. 1946 The enhancement of circulating antibody concentration by adrenal cortical hormones. J. Immunol. 52:101-112. Contrary - Eisen, H.N., Mayer, M.M., Moore, D.H., Tarr, R.R. and Stoerk, H.C. 1947 Failure of adrenal cortical activity to influence circulating antibodies and gamma globulin. Proc. Soc. Exper. Biol. and Med. 65:301-306. This discussion of the effect of cortisone on antibody production is of little use in trying to elucidate the biological basis. Effective cortisone on hypersensitivity is believed to result both from 1) inhibition of antibody formation 2) the anti-inflammatory effect. For example, ' the vascular lesions of experimental serum sickness can be suppressed by doses of cortisone too small to influence antibody response.'' (Germuth, F.G. Jr. 1953 The mechanism of action of cortisone in experimental hypersensitivity. 1. Hypersensitivi of the serum sickness type. J. Exper. Med. 98:1-12. ) " However, allergic skin tests in man are not suppressed. H-2 H-2 H-2 a i He ok H-2° H-29 H-2? Qo H-2A H-28 H-2D H-2p' H-2K H-28 H-2Q H-2P CDEFK cD EFk CDE Fk CD'E Fk CdEfK C*S"EPFk CO" Q" aFk C*Pp"n?k A C57BL, C57L, LP, 129Rr BALB/c, DBA/2, C57BL/6KS etc, YBR/R2, YBR/Wi CBA, C3H, C57BR/a, C57BR/cd, ST ASW DBA/1 P “> Gorer, P. A., 1956 Some Recent Work on Tumor Immunity, “Advances in Cancer Research, IV; 158, Gustafsson and Laurell: 1958 Gamma Globulins in Germ-Free Rats. J. Exp. Med. 102:251-258, His Summary. The methods of evaluation of Gamma-Globulin are somewhat dubious and the germ-free animals may have had from none to as much as one-fourth of the globulin level of the controls. The beta globulin was only slightly depressed and the total protein and albumin were normal. They conclude that the gut flora plays some role in stimulating globulin production. [ences breech Peete shaglbe Ay ew Pe ee Mo Abe eofrol, et, cable 48%, a (specs Le urther Evidence of indi rect srdect ion ef X-radiation of Lym a ytic Neoplasas in Wlce. J, t. Can. inst. 20:489.h93, Petter, 1958 Review of thymus neoplasms and in particular the work of Kaplan and Brown. According to Law and Potter '' the possibility of repopulation of AKR thymic grafts by (C3H x AKR) F, host cells. - Law, L.W. 1952 Increase in incidence of leukemia in hybrid mice bearing thymic transplants from a high leukemic strain. J. Nat. Cancer Inst. 12:789-805. Law and Potter had made thymic grafts into irradiated hosts and found that most of the tumors had come from the host and a smaller number of the tumors from the grafted tissue. Later Kaplan had done a similar experiment which indicated '' the tumor cells behaved genetically as if they were derived from cells of the implant.'' The present article is an extension of this study. Perhaps the point of didference is that in some of Kaplan's work the thymus was excised. A number of thymic grafts were made into the right axillary region after irradiation of the recipient. About half of the tumors were of host, half of recipient origin, thus substantially confirming Kaplan. The tumors were mainly lymphocytic, but see reference 10. (Dunn, T.B. 1954) "Exposure of young adult male rats to 400 r of whole-body x-radiation fails to inhibit the hyperplasia of reticuloendothelial cells induced by subsequent administration of trypan biue.!! These authors also failed to blockade the res by trypan blue and they criticize the general concept . HcMaster, Philip 0, Edwards, Joshua L., and Sturm, Ernest. 1955 Active Anaphylaxis te a Ferelgn Pretein induced in Mice by the Transfer ef Tissue from Animals Previeusly Injected with the Protein. J. Exp. Med. 1023119131. Loe? The main point on this is that BSA persisted in rabbit liver for at least six weeks as detected by the capacity to induce anaphylactic sensitivity in mice. By this time the serum was inactive. There is of course circulating antibody in the serum of these animals. There is no reference to persistence in other tissues. MBIK faba jofrt — Paddiel wee deg briettion nn prrcutis heelys BH! pion 19-4305 MEG Mefpa Xatag geves Ah Fah prt 4GsOn 180/80 dud — NaN arabs wth MEC se Af. shetees stelle wn sebagai diidkns ohare ard bbiianuplecc phim apolar L thes ror Makinodan, T., Gengozian, N. and Shekarchi, t. 1958 Rela- tive Effects of Splenic and &-: Sene-Marrow Cells on Lethal ly trradiated Mice. J. Nat. Can. Inst. 20:591-600. Still arguing about the etiology of runt disease. Set out to investigate mechanisms of antibody production after irradiation. Irradiated animals immediately after radiation received isologous spleen or bone marrow as well as an immunizing dose of rat blood cells. As one might expect there was a substantial response of the spleem treated animals and not of the bone marrow treated animals. The irradiated untreated mice all died within 13 days but both spleen and bone marrow were however effective. Heterologous spleen caused rapid death and heterologous bone marrow slowly increasing deaths uP to a period of 60 days. Two doses of heterologous spleen were used. 12 x 10’of-timmatth.cells (7) and 10 times this amount. The lower dose gave somewhat slower killing. When | refer to heterologous here 1! mean homologous strain of mice. "Only in preimmunized animals has it been reported that antibody-producing cells were detected in the bone marrow. Kolouch, F. Jr. 1938 Origin of bone marrow plasma cel! associated with allergic and immune states in the rabbit. Proc. Soc. Exper. Biol. and Med. 39:147-148. Askonas, B.A., and R.G. White 1956 Sites of antibody production in the guinea pig. The relation between in vitro synthesis of anti-ovalbumin and gamma globulin and distribution of antibody-containing plasma cells. Brit. J. Exper. Path. 37:61-74. "In an attempt to induce skin-graft tolerance by injection of adult homologous splenic cells into newborn mice, Billingham and Brent obtained comparable results. Billingham, R.E., and Brent, L. 1957 A simple method for inducing tolerance of skin homografts in mice. Transp}. Bull. 4:67-71. These treated newborn mice appeared normal for the first week or two but died soon after. They criticize the experiment of Uphoff (Uphoff, D.E. 1957 Genetic factors influencing irradiation protection by bone marrow. |. The F, hybrid effect. J. Nat. Cancer Inst. 19:123-130.) on the role of graft immunity to the host, but they appear to be back-tracking just a little bit. They feel more controlled experiments are necessary. Makinodan, T. and Gengozian, N. Primary Antibedy Response to a Bistantly Related Heterologous Antigen during Maximum Depress- fon Perlod efter Varying Doses - x Radiation. J. of tram. 8I: $s 150. . Mice were irradiated and sensitized to sheep rbc. The maximum depression of antibody response occurred when antigen was given within 24 hours after X-ray. The main effect was to greatly prolong the induction period. No effect of isolygous bone marrow on the induction period was found. They therefore conclude that normal bone marrow does not produce antibody forming cells. They did not however use bone marrow from sensitized donors. Gengozien, N. and Makinodan, T. Antigen Injection to Time of | Irradiation on Antibody Produc- tion In Mice. 1958 J. of im. 8Q: 189. ‘Maximum immunologic depression occurred in mice receiving antigens five minutes to one day after x irradiation. Although there was a progressive increase in the response to antigen as the interval between x irradiation and antigen injection was increased the immune mechanism of irradiated mice never returned to a completely normal status. Irradiation five days after antigen showed total titre above normal. These results are in conflice with the effects on rabbits which show complete inhibition of antibody formation. On p. 193 an index "relative immune status'' was made using four different measures of antibody effect. They found a reduction at maximum from 4 log, down to about | log, units when the antigen was given immediately after x-ray. up it Modu inst dete tye Logg p 3 ae xe Hus Tantiines bocohe Aoet bres ! 2S Hpk heme en we S fe (Poe Uda 17f. Bee Supper cers i] 4 PC peel ants B] ™ 7? ; Gre orden! ee Merdeslgers thirraccerong — (unt, Lif!) t pepe fT mrad f- HW flicwon (Wb neem “ame Spleen cells into irradiated mice of the a and the cba standard imbred strains. Effective colonization of the recipients was shown by the iso antigens of the graft in the spleen by virtue of their ability to sensitize new hosts to transplantation. He also demonstrated considerable but not total destruction of antibody forming ability of irradiated mice as against salmonella typbi h antigen. The immune cell s continued to produce antibody after transfer especially in irradiated as compared to normal recipients. Pre-immunized recipients showed considerably less production of continued antibody. YB Magen tPyrbad 199 Sume 12221272 Nossal, G.J.V., and Lois Larkin 1959 Failure to Induce Immunological Tolerance during Recovery from Irradiation. He gave mice 850 r of X-rays and rescued them with intravenous isolggous bone marrow in large amounts. Subsequently they were given injectsions twice per week of rat rbc. No tolerance was found although similar treatments of newborn mice will induce tolerances He may not have used large enough doses of irradiation, the bone marrow he used may have been responding to the antigen and this is not at all unlikely in view of the large amount, and in any case from Gengozian's results mice do not become completely unresponsive after irradiation. ¥. d, Yer avd Yawn 19))~ Odell T.T. Jr, F.G. Tausche, - 7 ~ . . D.L. kindsiey, and R.0. Owen, [ate drdy rvrdbrA— 4957 The Hemoetransp! antation CA ‘ef Functional Erythrepeletic CY :8M- Ff? 3 fb, Elements In the Rat Following . | 3/77. a) rat hurener rrd . 1 there ane eth Mths: eobbdy Aud — — ae i Have +Pasher : ae b) My 4 ran, worn ovimele wet thernlly pty] Buk A, AB) tech 22/8 arufls fom B. 24-Becege det Bheo, %[31 Ax A aces B! Haare Hire annals cecoverch ad thy to thant ? Thal A pf lf oA pha ar os fol mx ye ( Oy Hiary sey Uhr <> qyurgererfs ? Ao bottom Ay B ! ( theo ye Kviobces Hlranie rr ae. Pain He necend bo Pe pen EI Ty a Pith r etey aint dctsane witht bere marae? "eda Telaweet X aged, bar acrceudl race ? Ute Adlerad ararens ry hofP Ntlice faudignr (Parvre.) gues Axle, LA expncae 78 When rilltr- adebeefter, pi/ + frgpedoeaflce:prmemucbin her tyus = 12, © weeded G Speer Aunty Pook, elP/ oy, When Weerrtimsune, ants 2 ard tedbamny leds at ~ 10° Caclgbe MYT ablryes wakes hot hl A Wahine wkilrrbir pooky qrenps p FY. Vz Conglemend pajtd Aes >— 9 Hheronenty. abtealin co a abit bag parerctort legzpemermecen po13l (es — obo at ages Fisbayte Aeris rare) NOTES Rosenberg, L. T., Chandler, M.H. Gordon, A. S., and Fischel, £€.€. Antibody Production by Guinea Pig Cells Demonstrated by the Passive Cutaneous Anaphylaxis Reaction. 1958) J. of Imm. 81: 136-141, Authors transferred cells from guinea pigs pre-immunized to egg albumin. After 7 days various organs were removed and cells transferred. Reactions were obtained with "as few as 1,000,000 cells'' to sensitize the skin. Authors refer to this as PCA and this seems to be the same experiment as that by Chase on the transfer of hyper- sensitivity. The reactions were delayed for periods of 1-3 days which they account for on the basis of the amount of antibody persent. 1! am somewhat confused about the distinction between immediate and delayed hypersensitivity. 'In the present study the generation of immediate type hypersensitivity would appear to be dependent upon the structural integrity of the cell.'' The effectiveness of cel! extracts in transfer is controversial: Affirmative Waltzer, M.,2eBdwnan, K. L., and Stroyman, S., 1957, J. Allergy, 28:206. 2. 17,and negative Friedman (No. 18) Freedman, S$. A., Fisher, P., and Cooke, R. A., “1957, J. Allergy, 28:501. If all cells were active they indicate a rate of production of one molecule antibody per second per cell. The administration of cortisone to the recipients did not influence the reaction. He states that cortisone is already known to inhibit primary sensitization of the donor. Spleen cells were consistently effective; thymus occasionally effective in sensi- tizing recipient skin. Lymph node, bone marrow, circulating leukocytes, and liver did not sensitize. Santes, GoWey and L.J. Cole 1958 Effects ef Donor and Hest Lymph- eld and Myeloid Tissue injection in Lethally X-Irradiated Mice Treated with Rat Bene Marrew. J. Mat. Cancer Inst. 21:279-293. X-rayed mice were treated with rat bone marrow which by itself results in rppid rejection of the rat tissue and death. Claimed that the graft pereists longer if isologous liver, lysed or unlysed, and other lysed tissued are also injected. Survival of the mice is significantly shortened when spleen or thymus is injected with the rat bone marrow. "The most likely explanation is that the injected isologous spleen and thymus cells are capable of initiating an immunological response against the foreign rat tissues.!! , Trenton has shown that tolerance to homologous skin grafts induced by lethal irradiation and homolous bone marrow can be abolished by the injection of isologous lymph node or of spleen cells from an unirradiated animal of the host strain. Reviews antibody production by thymus and notes that the evidence for it is meager. This is mainly the work of the Harrises. He fefers however to Dixon and Stoner as affirmative. "It should be emphasized that the search has been for the production of antibodies of the arthis type and not for the delayed tuberculin type of sensitivity.'' This is presumably in reference to the effect of thymus in accelerating refection of rat bone marrow. Smith and Bridges: !mmunological unresponsiveness in Rabbits Produced by Neonatal Infection of Defined Antigens. J. Exp. Med. 102:227-250. Details in print, as requested. A single injection of BSA of from 10 to 100 mg induced tolerance lasting 90 to 120 days. Reinjection of antigen during these intervals gave in- definite prolongation of tolerance. Persistance of antigens could not be directly verified but is assumed the basis of these results. Page 245. The data presented would suggest that the critical antigen may be located intracellularly unavailable to passively administered antibody, (reference 13) since such antibody has no effect upon the un- responsive state. | don't recall that Dixon established this specific point and it should be looked up again. Item: The liver is a known site of prolonged persistance in the course of antibody production. (reference 43). He does not quote McMaster, which may give more data on this point. Item: The authors apparently have a clear picture that persistance of antigen must be considered the mechanism of continuation of tolerance. They feel that these conditions are not accounted for in current theories of immunity. Item: How should one tie in the incompetence of neonatal animals? The fact that even in an adult animal, which is immunological competent, the reappearance of active cells can be surpressed by reinjection of antigen would indicate that neonatal incompetence is not directly relevant. Item: These authors also failed to give tolerance to a number of bacterial antigens but they comment on the possible difficulty of sat- urating the responding system. Note: They used relatively small quantities to TAB vaccine, no more than ten to the eighth organism. Totefence f 1 jr Fe pacts fot elt "] " ? D2; FID Aptects CbLAbeL, OT et GEL), Gon ae eto Yossi fu rpc dag gobo adihdy poly To pin aden Ah fle GL Trl telat GE oy litrrickus rayerrer. pk lrcls be tds o> ne ’ anprle + pris derliargel TRE | st fed epee Og Pepecen lo. ‘ | bead eee ‘100 | “ ai lo Frorrcoret ok Trentin, J.J. 1957 The Immuno- logical Basis for induced Toler- ance to Skin Hemografts In oO irradiated Mice Recelving Bone Marrow Transfusions. Trans. ‘tulietin, A:7¥78. "The following unpublished data from this laboratory bear on point (d). A suspension of lymphocytes from lymph nodes and/or spleen of normal unimmunized adult CBA mice was injected intr-peritoneally and/or subcutaneously into mice of each of 3 experimental groups: (1) 10 CBA mice bearing skin autografts of 94 to 109 days durations. (2) 9 CBA mice bearing successful homografts of Cb skin (Balb/c without milk factor) of 162 to 182 days duration; the long survival was due to irradiation with 7%0 r. followed by transfusion with (Cb x CBA}F, hybrid marrow, 36 to 56 days prior to skin grafting. (3) 3 CBA mice bearing successful homografts of A skin of 101 to 150 days duration as a result of injection of A strain marrow during fetal life; the skin was grafted at 53 to 66 days of age, as in the experiments of Billingham et al#' Billingham, R.E., Brent, L., and Medawar, P.B. Nature 172:603, 1953. "No change in the skin grafts was noted during the first 2 weeks. By the 18th day however, signs of early breakdown were apparent in all 12 homografts (groups 2 and 3). Of the 9 Cb homografts (groups2) 5 underwent complete breakdown followed by death of the host, with reduced erythrocyte count in 4 cases; one was in early stages of breakdown when the host died of internal hemorrhage; another was in late stages of breakdown when the host died; the 2 remaining mice are alive, one with approximately 25 per cent breakdown, of the graft the other with apparent recovery after only slight initial breakdown. "Of the 3 A homografts (group 3), one has completely broken down, and 2 have almost completely broken down. No mortality or erythropenia has occurred in any of these 3 mice. Of the 10 autografts, none has broken down and none of the hosts has died.'! Trentin seems to believe that in these cases the maintenance of the graft is due to the absence of recovered lymphoid tissue in the host. However, there seems to be other quite good evidence of mixture of cell types so there still is an unsettled controversy here. if an 4 Pahun' SK -€. 1 Preclusion a secsadary oes ef irradia- then Syndrome by inoculation of Fetal Hematopoietic Tissue ‘Fellowing Lethal Tetal=Bedy X irradiation. je Mat. Cancer. Inst. 20: 625-632. Under certain, as yet undefined, conditions, a few animals may survive the reaction, whether it is initiated by the Graft or the host. The ability of a few animals to survive suggests the possibility that experimental conditions may be found which will preclude this Immune response, though to date various attempts to do so have met with little success.'' Congdon, C.C. and Urso, 1.S. 1957 Homologous bone marrow in the treatment of radiation injury in mice. Am. J. Path. 33: 749-767. Suggested using fetal hematopoetic tissue despite failure by Congdon and Urso just quoted. This is a preliminary report of successes. Used a BD hybrid and a B donor. Used a dose of 800 r and marrow from four bones on the one hand and homogenate of fetal liver and spleen from 6 or 7 embryos on the other. Implants were about 4,000,000 cells in each case. Adult marrow gives from 11-34 per cent survival at 90 days whereas the fetal marrow gave from 90-100 per cent. She may have induced tolerance in the implant. But there seems to have been no systematic study of the use of smaller doses of bone marrow. Uphoff, 0.€., and L.W. Law 1958 Ganetic Facters Influenc- ing irradiation Protection by compatibiiity-2 (H-2) Lecus J. Nat. Cancer inst. 20: 617- 6ah * Uphoff claimed that hybrid marrow affords better protection than marrow of either parental strain in a hybrid recipient. tn this study used cotsogenic lines. Homezygous 0D mice recieved inoculations of BB, DD, or hybrid BO marrow after 70O r total body x-ray. Results of reciprocal implants compatible with the hypothesis of a necessary graft versus host reaction. However the 90 day survivals were 45, 12, 69, 1 per cent for implant of DD, BB, DB, and none res- pectively into DD mice. Thus on the face of it the hybrid was even better than the isologous implant. With hybrid BD recipients the figures are 0, 44, 88, and o respectively. There is no particular explanation of these differences. pase eat 4 Wade 1% kfm (EE WHE: pwhh fabwidoor wudone a0 ) 70 reed”. Creedelanle IEP See Paryuee tor Ulige, © S 1932. 7 Prcechypral blows yynilly ref posed v T/e , rg myelin Mawes Madde yuma Teolont Paper ote Af LPL er YETY (02:67 Woke in ie tal tape eaalag Meena Malar dentin Teen Before am (Kite) sn ude llr wstirk erntio — "uw heh (Welsman ne — “fey! Aas Mod G see oS Sen = nununet Ap? - a “a gy ted A wat Lali ha aches Fe Luc Bx tt abel ie ee [igs ? Apna hregtcs H Brat! sricieces eo ale fh. ? dD. Hh ypecdaesifin”y. 7 m | ; ane, a0 : Abbe PE ey 7 vad de : a eT t1 bg cob | : re : mevneel mri Wt hianfedets > 77 flitn, : L Reza . Prunr fre a” redelyr,. , — shin scar eye Atl wnhtuster nent Awrerreel. w//s8 DELAYED HYPERSENSITIVITY____ (per Chase and Raffel) 1. Demonstrated by delayed reaction of skin, cornea & fibroblasts in T/C 2. Provoked in Tbe: by protein plus wax. Can also be developed by albumin plus wax best given intracutaneously. 3, Also contact sensnitivity to low mw compounds, exp. picryl chloride, which acc Raffel might interact with normal skin lipid. 4. Transferable only by cells., probably ljmphocytes 5. But acg Chase, regional sensitivity of skin argues for induced reactivity via some diffieuble substance. bayer f bedlbabdy?? Mormons etl end OHS Ara bercthcs mend bay vancda ling entry ? epocte f coratlo path Bp lowkawrerey na elle Ws Ib Keg pope tb Aylee IM + CPR Facer 195! per 73:1 t het Hote CH 64:99 1936. 7 le) ebro anjk Ts 68:74. — pe La 104-321 YL. 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