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1971). The data suggest that an immunologically crossreacting agent also exists in man. The existence of Iymphotropic papovaviruses shows the diversity of host range within this virus group. The presence of papovavirus-like particles in a human lymphoblastoid line (CCRF-SB) may indicate that Iymphotropic papovaviruses could represent a distinct subgroup of polyoma-like agents. It should be of interest to elucidate the possible role in the etiology of proliferative diseases, particuIarIy of the lymphopoietic system. Acknowledgments The skillful technical assistance of Mrs. Gabriele Menzel is gratefully acknowledged. This work was supported by the Deutsche Forschungsgemeinschaft (SFB 31 - Medizinische Virologie; Tumorentstehung und -Entwicklung). References Böcker JF, Tiedemann KH, Bornkamm GW, zur Hausen H (1980) Characterization of an EBV-like virus from African green monkey lymphoblasts. Virology 101:291-295 - Dugaiczyk A, BoyerHW, Goodman HM (1975) Digestion of Eco RI endonuclease - generated DNA fragments into linear and circular structures. J Mol Biol 96: 171-184 - Girard M, Marty L, Suarez F (1970) Capsid proteins of simian virus 40. Biochem Biophys Res Commun 40: 197-102 - Hirt B Gesteland RF (1971) Characterization of the proteins of SV 40 and polyoma virus. Lepetit coll Biol Med 2:98-103 - Klein G, Lindahl T, Jondal M, Leibold W, Menezes J, Nilson K, Sundström C (1974) Continuous lymphoid celllines with characteristics of B cells (bone-marrow derived) lacking the Epstein-Barr virus genome and derived from three human lymphomas. Proc Natl Acad Sei USA 71 :3283-3286 - Mueller-Lantzsch N, Georg B, Yamamoto N, zur Hausen H (1980) Epstein-Barr virus - induced proteins. II. Analysis of surface polypeptides from EBV-produeing and -superinfected cells by immunopreeipitation. Virology 102: 40 1-411-Southern EM (1975) Detection of speeific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol 98: 503-517 - zur Hausen H, Gissmann L (1979) Lymphotropic papovaviruses isolated from African green monkey and human cells. Med Microbiol Immunol (Ber!) 167: 137-153 - zur Hausen H, Gissmann L, Mincheva A, Böcker JF (1980) Characterization of a lymphotropic papovavirus. In: Essex M, Todaro G, zur Hausen H (eds) Viruses in naturally occuring cancer. Cold Spring Harbor Laboratory, New York, Vol. A, pp 365-372 206
Haematology and Blood Transfusion Vol. 26 <strong>Modern</strong> Trends in Human Leukemia IV Edited by Neth, Gallo, Graf, Mannweiler, Winkler © Springer-Verlag Berlin Heidelberg 1981 Immunopathology of the X-Linked Lymphoproliferative Syndrome* D. T. Purtilo A. Abstract The immunopathogenesis of 25 kindreds affecting 100 males with the X-linked lymphoproliferative syndrome (XLP) is being studied comprehensively by our registry and laboratory group. XLP is a combined variable immune deficiency with Epstein-Barr virus (EBV) induced phenotypes of: (1) fatal infectious mononuc1eosis (IM), (2) chronic IM progressive to malignant lymphoma, (3) acute IM progressive to acquired agammaglobulinemia or (4) malignant lymphoma. Cytogenetic studies of peripheral blood lymphocytes from 15 surviving males and 21 carrier females reveal random karyotype errors in several kindreds. Often polyc1onal Ig or selective IgM increases and lymphocytosis with plasmacytoid forms typifies the IM phenotypes. Weakly reactive EBV -specific antibodies are found and anti EB nuc1ear antigen is lacking. Antibodies to EBV are paradoxically elevated in female carriers. Initially all lymphoid tissues show immunoblastic proliferation with plasma cell differentiation and focal to extensive necrosis. Thymus gland and other lymphoid organs become depleted in T cell regions and Hassall's corpusc1es may become destroyed. Multinuc1eated giant cells may be seen destroying the corpusc1es or calcified corpusc1es are found. The lymphoid infiltrates and lesions resemble graft-versus-host response in the fatal IM phenotype. Extensive necrosis in lymph nodes and deficient Ig secretion of B-cells characterize acquired agammaglobulinemia phenotypes. The malignant lymphomas span the spectrum of B cell differentiation with most being * This study was supported in part by a grant from the National Institutes of Health, CA 23561-02 immunoblastic sarcomas. One case probably was monoc1onal thus far, others are being studied. EBV DNA hybridization of tissues from 7 patients with fatal IM revealed 1 to 20 EBV genome equivalents per cello The patients lacked appropriate EBV antibody responses. Our studies of XLP support the hypothesis that immune deficiency the EBV permits chronic and fatallymphoproliferative diseases in XLP following EBV infections. Owing to this knowledge, rational bases for prevention by genetic counseling and by providing high titer gammaglobulin and antiviral therapy is being attempted. B. Introduction Our studies of the X-linked lymphoproliferative syndrome demonstrate the interaction between genetic predisposition to oncogenesis triggered by an environmental agent (EBV) in immunodeficient males. Prior to discussing XLP, the immunopathogenesis of Burkitt lymphoma (BL) and IM is reviewed. The results of studies done by numerous investigators during the past two decades substantiate the view that EBV can be an oncogenic agent in immunodeficient individuals. Abrief historical review follows for focusing our discussion of EBV -induced oncogenesis in immune deficient persons. Denis Burkitt, working in tropical Africa, delineated a new malignant lymphoma which often involves the jaws or abdominal organs (Burkitt 1958). Endemic African Burkitt lymphoma (AfBL) is present in areas of hyperendemic malaria. A hematopathology committee of WHO has defined BL pathologically (Berard et al. 1969). 207
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Haematology and Blood Transfusion 2
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Dr. Rolf Neth, Universitäts-Kinder
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Participants of the Meeting Aaronso
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Kurth, R, Friedrich-Miescher-Labora
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Wilsede Scholarship Holders (Grante
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Preface Gut ist eine Lehrart, wo ma
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Personal and scientific discussion
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Acknowledgement We should like to t
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Wilsede, June 21 1978 Memorial Trib
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limiting benign lymphoproliferative
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this most unlikely, however (for re
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longer subject to the same control
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Bregula U, Wiener F, Harris H (1971
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fresh lymph node biopsies from ten
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Fig. 3. Binucleate mitosis in an ob
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y Fig. 4. Schematic diagram of post
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than that among patients with Stage
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Tests of binding affinity, agglutin
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N Engl J Med 297: 963-968 - Green I
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Clinical Aspects
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"ring chromosome". "Mar" is marker,
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191 chromosomally abnormal patients
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tumors of both African and non-Afri
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Haematology and Blood Transfusion V
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Retrospective group 26/93 evolved l
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Treatment
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advantage in terms of duration of f
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leukaemia. An analysis of 168 patie
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11. Treatment Program Chemotherapy
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efractory congestive heart failure
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period (Sequence II) was gene rally
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children with a multiple drug proto
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DAYS 1 5 10 15 20 25 30 35 , I I I
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Biologically Drug Outcome fit" sens
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may counterbalance the potential be
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Ht (0--0) 50 40 30 20 10 0 Platelet
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10 7 ,-----------------------------
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11. Haematological and Biochemical
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0\ 0\ INTERFERON ... 10 3 rl E "'
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("pre-B" phenotype) has been descri
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human bone marrow cells exhibit the
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10 9.,0 MBKCC .. .,4 B prot:oool 1'
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demann W, Büehner T, Arlin Z, Gee
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-...l 00 a-tLDRENS CAt«:ER S TU>Y
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prognostic characteristics under in
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significantly higher in HR} (14.5%,
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normal or elevated immunoglobulin l
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References Andreeff M, Darzynkiewic
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R GROUP 1 ( 1970 - 1971 ) 17 PTS. R
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Table 3. Influence of initial featu
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LIJ (f) a.. < -1 LIJ Q: u. 0 >- I-
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me nt indicated that additional the
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42:2123-2134 - Chessells JM, Cornbl
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Baum et al. 1979). This study was b
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1. 0 '--'1--" 0.9 e: o .- VI VI E C
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e: o e: 1. 0 ,.--...-- 1'"'\ ......
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In conclusion, we can state that th
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Haematology and Blood Transfnsion V
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INDUCTION VCR + PRED + ASNASE (wk 3
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SCHED.INT 1 MTX • ! Adria MTX •
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~ looh---------ooooc>----o---c>----
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Consoll- Irra .tlon t) .tlon Indu
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Highrisk Standard risk Table 1. Cli
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Cumulo/ive comp/el9 remission 1.0 .
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10° 8 = 6 ö 4 Non T Cell .~ :ö
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% SURVIVAL 100 ~ ~II 0 80 60 40 - -
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a) Percentage of donor cell mitoses
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Table 5. Results of bone marrow tra
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...... w N Table 7. Clinical result
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agent had to be added and that in t
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C. Chronic Myelogenous Leukemia The
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Patients with a suitable donor rece
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No. Recurrent Leukaemia Other death
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followed by dialysis against isoton
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HS, HL- Heme >_ 40 0 HS I ;:. =====
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knowing at present. These genes may
Page 167 and 168: esistance to antifolates. In Vitro
Page 169 and 170: a DNA probe specific for the gene t
Page 171 and 172: translocation between chromosomes 9
Page 173 and 174: Table 1. Subdivision of 1827 Myelo-
Page 175 and 176: NORMAL CELL ®
Page 177 and 178: some change of the primary type, in
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Page 181 and 182: F. Transformation of Mouse Bone Mar
Page 185 and 186: were carried out with 3H-MTX in the
Page 189 and 190: the lysozyme cDNA prepared from ovi
Page 193 and 194: et al. 1976). The BJAB cellline in
Page 195 and 196: dalton bands corresponding to light
Page 197 and 198: 1979). The EBV-carrying cell lines
Page 199 and 200: producer lines (DAUDI and P3HR-1),
Page 201 and 202: G, Giovanella B, Westman A, Stehlin
Page 205 and 206: Dc;bt CT + i J.I9 Raji; 1. i .. 100
Page 207 and 208: c. Discussion During infectious mon
Page 211 and 212: C. Nonepisomal Viral DNA We have us
Page 213 and 214: A 260 3.0 A B 1670 70 N2 2.0 c: E .
Page 215 and 216: vivo. Nature 260:302-306 - Kirk JTO
Page 217: Fig. 1. a Polyacrylamide gelelectro
Page 221 and 222: 1979). The lymphocyte subpopulation
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Page 225 and 226: Pope JH (1978) Long-term T cell-med
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Page 229 and 230: Charaeteristie Morphologie maturati
Page 231 and 232: after TPA-induction (Table 3). The
Page 233 and 234: PA (1978) Reactivity of a rabbit an
Page 235 and 236: Blood Monocyte. B lood Monocytes 1-
Page 239 and 240: and nonhistone proteins can serve a
Page 243 and 244: The findings of the evaluation of s
Page 245 and 246: Fig. 3. Tumor grawth of L 428 cells
Page 247 and 248: Cell biological and Immunological A
Page 249 and 250: consideration. Sanel (1973) obtaine
Page 251 and 252: endotoxin serum, were used. A parti
Page 253 and 254: monocytic leukemia cell line in cul
Page 255 and 256: B. Isolation, Characterization and
Page 259 and 260: don al hemopathies generally displa
Page 261 and 262: nitors. Blood Cells 6:595-607 - Min
Page 263 and 264: \I) ....I ....I IU Jl 200 r 100 90
Page 265 and 266: their haemopoietic cells' ability t
Page 267 and 268: normal normal ALL ALL ALL persons p
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64.5 { V)
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References Biermann E, Neth R, Gros
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ehambers, the growth pattern observ
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References Anderssen LC, 10kinen M,
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REH CELL UNE TO CALLb~Ö ~q~ V.M. c
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the macrophage series in which the
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Table 1. Production of factor depen
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Table 1. Characteristics of the adh
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Fig. 3. A human marrow culture at 6
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300 250 • HYPERPROLIFERATIVE PATT
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Fig. 9. Nonadherent population from
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The cobblestone areas were often no
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L (1976) Induction of colony format
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B. Materials and Methods J. Tissue
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Fig. 2. Ultrastructural appearance
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Table 1. Monoclonal antibody reacti
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al. 1979; Janossy et al. 1979) is e
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to which this is an exact replica o
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inger JL (1976) Distribution of la-
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I region antigens were found to be
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have been reported to be present on
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V. FunctionalAssays Assays for PHA
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Functional studies of UCHT1 separat
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40 ,...... (5 L.. C o u 30 .9 ~ .~
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with immunohistochemieal methods (L
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can be dissected by cloning. Utiliz
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Table 1. Origin and marker profile
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complete identity of gp 100 from no
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Table 1. Reaction of single anti se
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media. Following 24-h incubation, c
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nonleukemic eells (Greaves 1979). L
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Fig. 2. Cytocentrifuged smears of b
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Modification of amino-groups of hum
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disturb this balance in the directi
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The majority of human blood lymphoc
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of the EBV infected B cells. Howeve
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and immunoglobulins. J Immunol 120:
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" K 10 • j ~ ALL RNlL AL wtfh les
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tion akuter Leukämiezellen in "spo
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D. Results and Discussion J. Acute
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selectively responsive to different
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l1J ~ 100 ~ Q. ::) l1J Z 0 ~ z >- .
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Table 2. Growth inhibition of S49 e
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Reverse Infectious ASC/2X1Q6 transc
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munized animals to 1316 tumor cells
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Haematology and Blood Transfnsion V
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Fig. 3. Expression of retroviral gp
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pg70. J Exp Med 143: 151-166 - McGr
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Table 1. Expression of tumor antige
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Virological and Molecularbiological
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Table 1. Oncogenic properties of re
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also Fig. 1). It followed that the
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whether this sequence is related to
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zed in infected cells argue that th
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a specific viral transforming prote
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detect viral RNA as the only charac
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Eisen H (1980) Myeloproliferate vir
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p,60- -34K - 1 2 3 4 Fig. 1. In vit
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.. p - • a'T ... I .t'l Fig. 4. D
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Fig. 2. Photomicrographs of NY68 in
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DEAE (o(lJmn 'liI GI -2 2 o e s 1
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vity was deterrnined. For endogenou
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pr 180 - - - P 12/15 - A B c D E F
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85,- 66- -27 - -66 40- 27- -1'9 19-
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= 0.5 o E Q. o ILI 0.4 (J) « ILI .
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Table 1. Oncogenic potential of avi
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100 III GI c: o "8 80 > w
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Expt. No. Infecting virus Proportio
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Haematology and Blood 'fransfusion
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sequences, provided its gag portion
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77:3009-3013 - Hu SSF, Moscoviei C,
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RI 2.2 md and Hind III 2.6 md leuke
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RELATIONSHIP OF ENDOGENOUS AND EXOG
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E ........ E Cl. U E :::l .... Q) (
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References Astrin S (1978) Endogeno
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the same animal were examined (e.g.
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I) 'IQ a \0 - CL -- Fig. 2. Restrie
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~ ..................... ~ Cell 3' 5
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a :Sa,C! + . ~ 111 i' ( " '~ .J. b
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Table 1 Sampie Tissue TS fragment"
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a b Sac I / rep ._-_.-_ K J nl rep
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Haematology and Blood 'fiansfusion
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Osteopetrosis and osteosarcomas occ
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Lymphoma cellline Table 1. T and B
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Table 2. In vivo growth and oneogen
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Table 1. Transforming aetivity of c
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Table 3. Transformation aetivity of
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- Shoemaker C, Goff S, Gilboa E, Pa
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indieate a shifting of target eell
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Table 2. Expression of Jl and Sourc
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~ i ,..1---------,,':::::::::::::::
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fragment of pBR322 DNA, a 3.0-kbp S
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Mak TW (1979) Proc Natl Acad Sci US
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Table 1. Transformation of 3T3 cell
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inserts in the genome of rapidly tr
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pulations, it seemed likely that th
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contains antigens which react with
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le of reacting in sensitive radioim
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gic approach. In: Hiatt HH, Watson
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12 Eco R [ Fig. 1. Hybridization pa
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10 - '1~ )( -~ S:! E A U I o 1 2
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Haematology and Blood 'fransfusion
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cultures. These cells did not conta
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indication of malignant T-cells in
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Fig. 3. Thin-section electron micro
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Table 3. Lack of detectable related
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J. HTLV Was Present in the Primary
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specific signals into nonspecific s
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Table 2. Distribution of HTLV-relat
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u 10 ~ 20 ~ :c 30 a 40 o Fig. 1. Ki
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SSV TrS-gp labeled effectively with
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60 HFF/SSV cDNA CELL RNAs: 0 HF/SSV
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Antisera a Table 1. Immunofluoresce
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Haematology and Blood 'ftansfusion
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y competition RIA yielded virtually
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SiS'V' gp70: ANTIGEN, ANTI BODY, IM
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type-C virus p30 antigen in cells f
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c. Results The fractionated whole-b
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induced antibodies as well as exper
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- Fig. la-f. Retravirus particles p
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eplication of infecting murine leuk
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immunodeficiency, multic10nal lymph
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Bovine leukemia --, proteins of 499
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Human T- cell - -, characterization
Page 563 and 564:
RNA -, of tumor virus 439 Rous sarc
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Haematology andBlood Transfusion Su
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