" . oic. I",. - - _ _ _ _ _ _ _ _ _ _ -- _---- -____-_- ___.___ -- DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE ---- PUBLIC HEALTH SERVICE APPLlCATlON FROM. 12/01/69 THROUGH: 11/30/74 RECJUESTED BUDGET PERIOD FOR CONTINUATION GRANT I FROM: 12/01/71 THROUGH: 11/30/72 __ TOFG~~>IED BY APP~ICAN r. --- CHECK INF@RMATION IN ITEMS 9 THROUGH 6. ~-l~~~FURN(SHCDRRE~~fOHMATION IN JTEM 13. _____-_.- ----- ___- --P-w _--- 1. TITLE GEhETICS OF: I-lU~`tAAi\l TISSUE XXXXXXB ANTIGENS LEDEKBtKC, JGSHUA STANFORD UNIVERiIiY DEPT OF GENETICS STANFORD, CALI FdRNIA 943c)s STANFURD UtvIVERSITY SCH OF MfD STAhFORD, CAL.IF F--T------ . C'sGREL Ph.D. --- ------?`;, ~?---&i~=jfiT NUMBER 45i12 1o ---- ------ 20. DEPARTME-N?:cE, LABORATORY OR EQUIVALENT I 6. TjTi~~4D[)R~ OFFICIAL IN BU5lNESS OFFICE OF APPLICANT ORGANIZATION GENETICS ZC. MAJOR SUEiDtVlSlON I CONTROLLER SCtliJOL UF MEDlCIiJf STANFUR UNIVERSITY 3. ORGANIZ~N~OMPONENT TO RECFIVE CREDIT FOR ST ANFOKD, CALIFOHIUIA 9436-5 INSTITUTIONAL GRAYT PURPOSES 01 SCiiUDL OF MfDIClNE -~- --- --- ----. -- COMPLETE THE FOLLOWING (See Instructions) -----....--- 7 RESEARCH INVOLVING HUMAN SUBJECTS (SW Instrtrrrran~) --_---- 8. INVENTION CERTIFICATION (Src Irrafn~clronsJ UN@ UYES =NO u YES-NOT PREVIOUSI Y APPROVED: - REPORTLD DATE a YES-PREVIOUSLY HEPORTEO --- --- 9. PERFORMANCE SITE IS1 Genetics Department Stanford University School of Medicine Stanford, California STRATIVE OFFICIAL IITEH 156) ----.-- ---- IQ. O'RECT CCSTS REQUESTED FOR BUDGET PERIOD ---- --I -_u-------- Ii*. CONGRESSIONAL DISTRICT OF APPLICANT iZT COUNTY 5cAPPLlcANT ORGANIZATION SHOWN IN ITEL! 4 ORGLNIZATION SHOWN IN ITEM 4 Tenth Santa Clara Note correction of spelling in title, Item 1. Item 2B - add degree. Item 2C - Dr. Lederberg's Sot. Sec. No. aded. - -----------~ :c. CERTIFICAT:ON AN0 A'CEPTANCE. WE THE UHOERSIGNE,. CERTIFY T",, THE STATEt.$E'dTS HEREIN AIE TR?IE AND COMPLETE TO TqE GEST OF OUR KNO'HLEOGE Ah0 ,hCCEPT a5 TO A.HV GRANT AUVAROEO. THE On;IGA710N TO COMPLV WrTH PUBLIC HEALTH SERVICE TERMS AX0 CONOITIONS *h EfFECi I. At THE TIME OF THE AXARD. I,' SIGNATURES , I --_- -----_-- -----.-I- I - FHj z590-' OPTIONAL REV, l-70 RETkN CUMPLETEIS APPLlCATlOh T3 PHS !JEF[liZE: 1 UCTclSEY 1971 SECT[fJN I[-;aij5GET (USUALLY 12 MWTHS) ~---___.____ _.~-~__--L11/301_7_2 A. ITEM!:F CIHECT COSTS REQUFSTEI! FOR NEXT BUDGET PERIOD _____ --~ -__.--- KRSONNEL ___~--- ---- -- NAME (Last, rd, Inllial) -----I ,a, y-1 _-._ -----.-__ __ ~.____.__----__---.- _.-.--I^_~- Lederberg, J. PRINCIPAI. INVESTIGATOR none _____--__-__------ --- ___._-__---.- ,J. liwan~, --.-!i6 1 - Scientific Progxamrlier 75% ._-3,600 __ --_ - &np,, L. .-~_-w...w~..,S_r_~R~Asst 0 --2JnQ 467 _~ -.Ah~pzAxA&xzkUr Leo. ?I. Xii. 2+QL!fv--.-.-__-e. 311 _--_- -~-- - Staff benefits: __--.--.. -.-.-- - ________ .-- --- ___- _____. --_--------- 9 mo. @ .7.5.2X _____-..--- --.. ___-- _--- 3 mo.,@ 3.6.7% ~. ; - .- ___-_ -_.--.-___-- __~---.-~~-- -- -- --- --. ---__ - --.- _I_--- --~ --- - ~._~__ __-.___- i -.- ~_-------_-----..--_ _--__ ---- - .__ __..~ -____ Subtotals - -___---_. - ___.~ !iS,liQL~s1,3 39 _-. (Indicate cost of each item listed below) --- ~.-- CONSULTANT COSTS (See Instructions) TOTAL (Columns (d) arid (e) -* EQUIPMENT -__- __-- ___- .~ .- 5 : _.-_-_ -- -. .a 5 SECTIDN II ___ ._.____._ -_----.___-- -^ ------ --- -- -__---- SUPPLIES Culture medium and cbgmical-5 300 - -___ DOMESTIC TRAVEL I- -- --__. FOREIGN -__ I------- PATIENT COSTS (See instwctions) ALTERATIONS AND RENOVATIONS OTHER EXPENStS (Itemize) Computer Time $4,000 Communications, Publication costs 200 TOTAL DIRECT COST (Enter on Page 1, Item 10) ------l------- ---- __ ___-.- TOTAL 4 514,439 INDIRECT COST (See Instruct8Jns) .-..?b S&W' Date of DHEW Agreement: 46 0 v."Dc. 2124171 _~.~ - --_,RII -- --_- ____-_ *If this is a spc'lial rate (e.2 off.?ite), explam. _ .._____ __- 0 Not Requested 0 Under negct:e:ion vvlth. -____.---. PHS 2590-l (All prevrous e&tioPs obsolete) Rev. 1.70 PAGE 2 SECTIOH II (Ccntin!Jed) SECTION IL-BUDGET (Continued) Grant Number 1 G?l-14650-06 ___I-. f3. Supplemental information regarding ITEMS in the proposed budget for the naxt period which require explanation or justification. (See InStrUCtiOnS) The major emphasis of the work supported will be in connection with the continuing computer analysis of our serological data on the HL-A system. Mrs. Hwang has been largely responsible for the development of our system of programs and continues, with the help of Mrs. Leo, to supervise the analysis of our data. During the coming year we will be obtaining data on the frequencies of HL-A antigens in a variety of populations,and also different disease states, specifically Hodgkin's disease and systemic lupus erythematosus. The experimental work is being done in collaboration with Drs. PlcDevitt and Grumet of the Department of Medicine. In addition, our system of programs is used by Dr. Rose Payne of the Department of Medicine, who was closely associated with Dr. Bodmer when he was at Stanford. A small amount of experimental work connected with the carrel.ation of HL-A typing on fibroblasts and lymphocytes is being carri-ed on by Mrs. Wang. This represents a continuation of the studies started by Dr. Bodmer when he was at Stanford. Because the staff benefit rate has increased over that previously anticipated, total direct costs are slightly more than the previously recommended amount. PHS-259C-1 (All previous edltions obsolete) REV. 1.70 PAGE 3 SECTION III / ~~n/v;;72 __ GR~;~:~~;;o-06 1 The following pertains to your CURRENT Pf-fS budget. ho not include cost sharing funds. This information in conjunction with that provided on Pale 2 will be used in determining the amount of support for the NEXT budget Period. ACTUAL ESTIMATED %I~~~; tXPE;,NDl;URES ADDlT!ONAL TOTAL ESTIMATED ESTIA!ATED EXPEfiUITURES AND EXPEfiDITURES L?~OBi.IGATED OBl IGATIONS FOR AND OBLIGATIONS BALAkCE A. DUDGET CATEGORIES (As apprwed by 7/31/71 __-.- -.-. __. REMAINDER (Smract cot. 4 awarding unit) (Insert Date) Of CURRENT w: 3";"' from Cal. 1) (1) (2) BUDGE~S~ERIOD (4) (5) Personnel (Salaries) 13,890 7,338 6,552 13,890 o- ~- Fringe Benefits Consultant Costs Equipment --- Supplies Domestic TRAVEL _ Foreign 1,952 1,020 955 1,975 -23 -- -- .- 3,000 2,400 900 3,300 -300 Patient Costs 1,000 200 0 200 800 --- Alterations and Penovations -- Other 12,100 6,335 6,242 12,577 -477 Total Direct Costs 31,942 17,293 14,649 31,942 0 - Indirect Costs (If included in award) 8,195 4,329 3,866 8,195 0 TOTALS * $40,137 "21,622 $18,515 $40,1.37 B 0 Use space below to: B. List al! items of equipment purchased or expected to be purchased during this budget period which have a unit Cost of $1000 Or more. C. Explain any significant balance or deficit shown in any category of ColUmn 5. El. List all other reseal-ch support for Principal Investigator by source, project title, and annual amount. The taking of blood and tissue samples has for the most part been completed, so there will be a balance left in the "Patient Cost" allocation. However, this is more than offset by costs related to the analysis of the samples and computerization of the data. Research Support: (NIH) AI-5160 Genetics of Bacteria $56,000 p.a. -- _--- ;;;2;-9;1 (All previous ed!!rons obsolete) PAGE 4 (use Gontmua!ron Pages as neoessary) SECTION IV APPLICANT: REPEAT GRANT NUMUER SliOilrN ON PALE 1 __d ----l----- - GRANT NUM@ER SECTION IV-SUMMARY PROGRESS REPORT I GM-14650-OG --- PRINCIPAL INVEST ICATOR OR PROGRAM DIRECTOR (Last, First. Initial) Lederberg, Joshua NAME OF ORGANIZATION Stanford University TITLE (Repeat title shown In Item 1 on first page) ----- PERIOD COYFHEC BY THiS REPORT -_c FROM ?HR~UGH 12/l/71 I 11/3Qj72 Genetics of Human Tissue Antigens ---- 1. List publications: (a) published and not previously reported; (b) in press, Provide five reprints if not previously submitted. 2. List all additions and deletions in professional personnel and any changes in effort. 3. Progress Report. (See Instructions) 1. Publications. - Santachiara, A.S., M, Nabholz, V. Miggiano, A. J. Darlington and W. F. Bodmer, 1970. Genetic analysis with man-mouse hybrids: linkage between human lactate dehydrogenase B and peptidase 6. Nature 227: 248-251. Bodmer, J.G. and W. F, Bodmer, 1970. Studies on African Pygmies. IV: A comparative study of the HL-A polymorphism in the Babinga Pygmies and other African and Caucasian populations. Am. Journ. Hum. Genet. 22: 396-411. Miggiano, V.C., M. Nabholz and W. F. Bodmer, 1970. Detection of HL-A and other antigens on fibroblast micro-monolayers using a fluorochromatic cytotoxicity assay. Histocompatibility Testing, 1970, 623-629. Gabb., B.W. and W. F. Bodmer, 1970. A micro complement fixation test for platelet antibodies. Histocompatibility Testing, 1970, 543-547. Bodmer, .I., A. Coukell, W. F. Bodmer, R. Payne and E. Shanbrom, 1970. A new allele for the LA-series of HL-A antigens: the analysis of a complex serum. Mistocompat- ibility Testing, 1970, 175-185. ' Bodmer, W. F., J. G. Bodmer and M. Tripp, 1970. Recombination between the LA and 4 loci of the HL-A system. Histocompatibility Testing 1970, 187-191. Mattiuz, P. L., D. Ihde, A. Piazza, R. Ceppellini and W. F, Bodmer, 1970. New approaches to the population genetic and segregation analysis of the HL-A system. Histocompatibility Testing 1970, 193-205. Hulett, R., A. Coukell and W. F. Bodmer, 1970. Tissue typing instrumentation using the fluorochromatic cytocoxicity assay. Transplantation 10: 135-137. Payne, R., J. Bodmer, W. F. Bodmer and E. Shanbrom, 1970. Production of defined human leukocyte typing sera. Histocompatibility Testing, 1970, 207-220. Coukell, A., J. G. Bodmer and W. F. Bodmer, 1971. HL-A types of forty-four Hodgkins patients. Transplantation Proc. (in press) McDevitt, H.O. and W. F. Bodmer, 1971. Histocompatibility antigens, immune respon- siveness and susceptibility to disease. American Journal of Med. (in press) Grumet, F.C., A. Coukell, J. G. Bodmer, W. F. Bodmer and H.O. McDevitt, 1971. Histocompatibility antigens associated with systemic lupus erythematosis: :! possible genetic predisposition to disease. New England J. Med. (in press) 2. Per budget. -- f;$Z:ap61 (All prewous emtions obsolete) PAGE 5 (Use Continoabon Page as necessary) ---- Application for Continuation Grant GM-14650-06 3. Progress Report (GM-14650-05) During the current grant year, the major part of Dr. Bodmer's activities was transferred to the University of Oxford where,he has taken up a posi- tion as Professor of Genetics. Experimental work was continued at Stanford by Mrs. Anne Coukell, and the Stanford Medical School's ACME computer facility continued to be used for our data analysis, while Professor Lederberg took over as principal investigator on the project from January 1, 1971. A major emphasis of our work during the year has been on the association between HL-A and diseases, specifically lupus erythematosis and Hodgkins disease. In collaboration with Drs. I!cDevitt and Grumet, we have confirmed the very significant increase in the frequency of the antigen W15 in patients with lupus erythematosis. There were some puzzling anomalies in the typing of these patients which will be followed up by family studies to confirm their antigen phenotype and further serological studies on the nature of the autolymphocytotoxic antibody present in the sera of many of these patients. Typing of forty-four Hodgkins patients from Dr. Henry Kaplan's clinic at Stanford did not indicate the previously reported increase in the antigens W5 or HL-A5 in these patients. However, it appears likely that this may be because the distribution of types of Hodgkins is different in the patients that we typed. Specifically, these seemed to include a much higher frequency of the nodular sclerosing type of the disease than is normally found in other series. We are again participating in the next International Histocompatibility Testing Workshop, whose aim is to obtain as comprehensive information as possible on the distribution of the HL-A antigens in different populations. We took part in the testing of sera to be used by the participants in this Workshop and prepared a specially absorbed serum for the detection of a component of one of the newer antigens of the LA series. We have greatly simplified our procedures for collecting, storing and shipping lymphocytes for typing so that they now require a minimum of processing in the field. This has enabled us to collaborate much more easily with workers in out-of-the-way places in order to obtain blood samples for HL-A typing. Page 6 PUBLIC HEALTH SERVICE - -. -- TITLE OF PROJECT Genetics of Human Tissue Antigens -.-----------~--- -- _-.___----__- GIVE NAMES DEPARTMENTS AND OFFICIAL TITLES OF PRINCIPAL INVESTIGATORS OR FROJECT DIRECTORS AND ALL OTHER PROFESSIOtiAL PERSONNEL'ENGAGED ON THE PROJECT. Joshua Lederberg, Professor, Department of Genetics * Valter F. Bodmer, Professor, Laboratory of Genetics, Oxford University Rose Payne, Sr. Research Associate, Department of Medicine H~~sHr~~~Hr~~K~~~~~~~~~~~ ~~,~yK~.~~~~~~~~~~~~K~~~~~~~~~~~~~~ ___- -____-. ___ ___.__---._-.-- NAME AND ADDRESS OF APPLICANT INSTITUTION Stanford University, Stanford, California 94305 ~.- --------- ----- ---- -%AMARY OF PROPOSED WORK - (200 words or less - Omit Coni~dent,o/ data.) In the Science Information Exchon~e summaries of b,;ork in progress ore exchanged with government and private agencies supporting research in the bio-sciences and ore forwarded to investigotorr who request such information. Your summary is to be used for these purposes. The main aim of this research program .is to further the understanding of the inheritance of antigenic differences of human leukocytes and other human tissues and to use these antigens for studies in somatic cell genetics. Cytotoxicity assays are being used together with intensive absorption studies of sera reacting with human leukocytes for the investigation of the genetics of the major human leukocyte antigen polymorphisms. Studies on the distribution of these antigens in various racial groups will also be undertaken. The specificities of antigens carried by permanent and primary cell culture lines are being investigated. The use of these antigens for studies in somatic cell genetics are being explored. School 0 8/16/71 DO fiOT WHITE BEL.U'H' THIS LINE -FOR OFFICE USE ONLY i _--- SUPPORTING AGENCY i ' I :/ --- -------------L+ METHOD OF SUPPORT (Check one) 0 Agency Stofi Negotlotcd (Intromurol) CI -_- __-___.--- FUNDS OBLIGATED CURRENT F.Y. GEYOND CURRENT FISCAL YEAR PHS. 166 REV. 5-70