Pan American Health Organization

ADVISORY COMMITTEE ON MEDICAL RESEARCH

Sixth Meeting

Washington, D.C. 12-16 June 1967

Item 14.1 of the Agenda

PAHO/WHO IMMUNOLOGY RESEARCH AND TRAINING CENTER

IN BRAZIL

Ref: RES 6/15

31 May 1967

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PAN AMERICAN HEALTH ORGANIZATIONPan American Sanitary Bureau, Regional Office of the

WORLD HEALTH ORGANIZATION

Washington, D.C.

RES 6/15

PAHO/WHO IMMUNOLOGY RESEARCH AND TRAINING CENTER

IN BRAZIL*

1. Origin and Scope

After having created a WHO Center for Research and Training

in Immunology in the Department of Chemical Pathology, University

College Hospital, Ibadan, Nigeria, in 1964, WHO decided to explore

the possibility of establishing another Center in South America. A

trip to South American countries was, therefore, undertaken by Dr. H.

C. Goodman, Head of the WHO Immunology Unit in Geneva, together with

Prof. Niels K. Jerne, then Professor of Microbiology and Chairman of

the Department of Microbiology, School of Medicine, University of

Pittsburgh, U.S.A. Following the report presented by these experts,

a sec9nd center was established in the Department of Microbiology and

Immunology, Escola Paulista de Medicina, Sao Paulo, Brazil, under the

supervision of Prof. Otto Bier.

The PAHO/WHO Immunology Research and Training Center in Brazil

initiated its activities on 14 March 1966 with the double aim of

providing:

1.1 post-graduate teaching in basic immunology, and

1.2 developing immunological or research projects directlyor indirectly related to public health problems ofthe country.

A first course was given during March 1966 to March 1967 and a

second course was started on 17 April 1967.

* Prepared for the Sixth Meeting of the PAHO Advisory Committee on MedicalResearch, 12-16 June 1967, by Committee'Member Dr. Otto BEer.

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2. BudRet

The income for the operation of the Center in 1966 came mainly

from three sources: WHO/PAHO, CAPES-Ford Program and Escola Paulista

de Medicina.

2.1 WHO has contributed its expert advice, and fumds for the

purchase of equipment and for the participation of one. Visiting Professo:r

and one senior technician. PAHO has also contributed with the traveling '-

expenses of an additional visiting professor from the U.SoA.

2.2 The CAPES-Ford Program covered the fellowship 's needed for

thé students admitted to 'the Center.

2- .3 Finally, the Escola Paulista de Medicina, offered teaching

and research laboratories covering a total area of approximately 500

square meters, and the services of the permanent members of the staff,

three of whom are on a full time basis with the Center.

Table 1 gives a resume of the expenses of the Center in 1966

with a breakdown of the several sources of income.

It may be pertinent to emphasize that the basic policy adopted

by WHO is not to supplement salaries of members of local staff, except in ' *;

very special cases and on a temporary basis. Otherwise, the Director of

the Center is entirely free in utilizing the money provided by the WHO

contract. This ·is lways done however, after consultation with Drs. H. -

C. Goodman and Zdenek Trnka, of the Immunology Unit of WHO, Geneva, and

this close cooperation proves extremely valuable in operating the Center.

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TABLE 1 SOURCES AD ILZ ION OF INOME-3-TABLE 1 SOURCES AND UTILIZAT ION OF INCOME

Amount* inSources US$ Utilization

WHO 22,000 1 visiting professor for aperiod of 5 months; 1 seniortechnician for a period of4 months; drugs and equipment.

PAHO 670 1 visiting professor: airtravel only.

CAPES-Ford 11,0ooo 6 fellowships for students,and installation of a coldroom.

Escola Paulista deMedicina 25,000 Salaries of 1 professor and

3 assistant professors; drugs,glassware and equipment.

TOTAL 58,670

* The figures are approximate and are1US$ - NCr$2,20.

calculated on the basis of

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3. Selection of Students

The CAPES-Ford Program does not relate in any way to the

selection of fellowship candidates, leaving it entirely to the Director

of the Center.

Selection is made on the basis of interviews which will try

to determine whether:,

3.1 The candidate is able to keep up with the activities of

the Center; . _

3.2 The candidate. is is likely to be assigned to teaching or

research activities in universities or scientific institutes throughout

the country after his training.

A third consideration is the desirability of having candidates

from different countries so as to fill the needs for immunology

teaching staff, as well as to provide scientific manpower to carry out

immunological researches of local importance.

4. Teaching Program in 1966

4.1 Visiting Professors

The course initiated in 1966 had the cooperation of 2

outstanding visiting professors, Dr. E. U. Beutner, Associate Professor,

Department of Bacteriology and Immunology, School of Medicine, State C ~

University of New York at Buffalo, Buffalo, N, Y., U.S.A. and Dr. J.* -g.

Uriel, Institut de Recherches Scientifiques sur le Cancer, Villejuif .

(Seine), France.

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Dr. Beutner took charge of the teaching of immunofluorescence,

from April 11 to May 6, and Dr. Uriel stayed for a period of approximately

5 months, from July 18 to December 15, being mainly concerned with

immunodiffusion methods and the immunoelectrophoretic characterization of

enzymes. The rest of the program was developed by Prof. Otto Bier and

the senior Assistant Professor of the Department, Dra. Maria Siqueira,

:with the help of Dr. H. Co Passos.

4.2 List of Students

Six students were admitted in 196(

Luis S. Prigenzi, M.D.

Paraguassú A.P. NOthen,Biochemist,

Adenir Perini, Biochemist

Edda de Rizzo, Biologist

Marisa Della SantinaBiochemist

Maria Carolina S. Guimaraes,M.Do

Assistant Professor of ClinicalMedicine, Sorocaba MedicalSchool, Sorocaba, S.P., Brazil.

Instructor of Microbiology,School of Pharmacy and Bio-chemistry, Univer. of SantaMaria, Rio Grande do Sul,Brazil.

Instructor of Microbiology,Escola Paulista de Medicina,Sao Paulo

Butantan Institute, Sao Paulo.

Butantan Institute, Sao Paulo

Department of Clinical MedicineEscola Paulista de Medicina,Sao Paulo.

4.3 Teaching Program

The program developed for the 1966 course is outlined in Table 2

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TABLE 2 TEACHING PROGRAM IN 1966

Date Lectures Laboratory Exercises

April 11 -May 6

May 9 - 31

Physical Methods

PotentiometrySpectrophotometryChromatographyElectrophoresis

Immunofluorescence

IntroductionPrinciples of IFQuantitative StudiesApplications

Chemical Methods

pH determination; Indicators;Visible light and UV spectrophotometry;Column and paper chromatography;Paper electrophoresis.

Fractionation of serum proteins;Fluorescent labelling;Characterization and standardization

of labelled antibodies;Quantitation of IF staining;Demonstration of nuclear antibodies;Demonstration of Streptococcus and Tre-ponema Pallidum antibodies;

Special projectso

Micro-Kjeldahl;Estimation of protein by UV spectropho-

tometry, Folin-Ciocalteu and biuret;Preparation of Azo- and DNP-proteinso

March 14 -April 9

Precipitin Reaction

Quantitative StudyMechanismApplicationsToxin-antitoxinNon-precipitating Ab

Method of Heidelberger & Kendall.Modified ABC method,Ramon Flocculation,In vivo titration of antitoxins;Special projectsoa

July 1 - 15· VACATION PERIOD

July 18 - 30 Proteins in' eneral

Plasma proteins

Preparation of gamma (gamma2) globulin;Purification by DEAE chromatography andSephadex filtration;

Lyophilization;Pervaporationo

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TABLE 2, conto

Date Lectures Laboratory Exercises,~~

.. . .. .

August 1 -

31Gel-precipitation

FundamentalsApplications

Oudin and Ouchterlony techniques;Determination of diffusion constant by

immunodiffusion.

Inhibition Reactiorns

Aloypes

Immunoelectrophoresis

FundamentalsApplications

Equilibrium dialysis;Inhibition reactions with sugars;Special projects.

IE of normal and pathological human

sera;Special projectsa

Enzvmes, general

Characterization ofenzymes by IE

Origin of antibodies

Structure of antibodies

Antigenicity and immu-nogenecityl

IE separation of enzymeso

Special projects.

Separation of IgG, IgA and IgMoSeparation of IgG 1 and 2Fragments and chains of antibody°Starch-gel electrophoresisoSpecial projects°

VACATION PERIOD

Complement

C' fixation

Preparation of intermediate complexeswith EA and C'

Identification of beta-1C

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September1 - 30

October

1 - 31

November1 - 30

December1 - 31

January2 - 31

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TABLE 2, conto

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Date Lectures Laboratory Exercisesi iii , i i i i , iii i~~~~~~~~~~~~~~.

Quantitative C'F by the method ofMayer et al.

Hypersensitivity

Role of C' in hyper-sensitivity

Measurement of RESactivity

Anaphylactic reaction of isolated mus-cleo

Passive Arthus and PCA.Degranulation of mastocytes.Reactions produced by aggrega;ted gammaglo

Plate CtFo Passive hemolysisoBlood clearance of C particles.

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FINAL EXAMINATION

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4.4 Examinations

Students were subject to partial examinations by Drs. E. H.

Beutner and J. Uriel, as well as to a final examination at the end of

the course by Dr. Z. Trnka, WHO Unit, Geneva, who came specially to

Sao Paulo for that purpose.

All students passed the examination. WHO grants will be

awarded to the two best students for further specialization abroad.

One of these students, probably by the end of this year, will develop

immunochemical studies on suhistsoúmiasisin the laboratory of Dr. Elvin

H. Kabat, College of Physicians and Surgeons, Columbia University, New

York. Both students were given permanent staff positions in the Department

of Microbiology and Parasitology, Escola Paulista de Medicina.

5. Research

5.1 Research projects assigned to students

Besides lectures, seminars and laboratory exercises, as lised

in table 2, research projects were also assigned to students. The choice

of the project was determined by the interest demonstrated by students

in special fields, as well as by future activities to be carried on by

them after returning to the institutions from which they came. For

instance, a project on the chromatographic separation and immunoelectro-

phoretic characterization of enzymes in human normal or pathological

pancreas was assigned to a student whose future activities were to be

developed at the Department of Medicine, Escola Paulista de Medicina.

Two students belonging to Butantan Institute were charged with the

characterization of venoms by immunodiffusion and immunoelectrophoretic

techniques. A third prbject, perhaps the most important one, dealt with

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the demonstration of autoantibodies in Pemphigus foliaceus ('Togo

Selvagem"), a disease that constitutes a serious public health problem

for which there is in Sao Paulo a special hospital caring for 200

patients.

The results of these two last projecta are ready for publication.

Table 3 gives a list of the projects developed in 1966, as well

as of those already assigned to students in the 1967 course.

TABLE 3 RESEARCH PROGRAM IN 1966 AND 1967 -

Student ¡ Research project Obbérvations

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1966S. Prigenzi

P.A.P. N6then

M. Della Santina t& E. de Rizzo j

*M.C.S. Guimarases

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iAdenir Perini

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Antibodies against intercellular subs-tance of stratified epithelium in Pem-phigus foliaceus ('Togo Selvagem").

Inactivation of guinea pig complement:in buffers of low ionic strength

Immunoelectrophoretic characterizationof enzymes in the venom of Bothrops ja-raraca.

Enzymatic content of human normal andpathological pancreas as revelaed byimmunoelectrophoretic techniques.

nzymes of cercarial and aof Schistosoma mansoni s

cterized by immunoelectrctechniques

E.H. Beutrer,W. Hale, C.A.Leme and 0.Bier col. Readyfor publication

Beihg writtenas doctoralthesis.

Submitted forpublication in"Science ".

Research inprogress

idult $ Research inla s progress .

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Table 3 Cont.

Student Research Project Observations

1967

L.S. Prigenzi & Therapeutic assay of Imuran in Pem- E.H. Beutner, C.A.P. Leser phigus foliaceus, its effect on auto- Leme, P. Leser and

antibody titer. 0. Bier col.. Inprogress.

F. Andrade praga Immunofluorescent and serological To be initiated instudies in calazar. May 1967.

M. Medeiros Mon- Project to be aosigned.taia

Mitsuko Akashi Project to be assigned

Adenir Perini & Immunofluorescent and immunochemical To be initiatedEnnio A. Naves studies in schistosomiasis. in May 1967

E. C8rti Passos Localization of aggregated gamma M. Siqueira and 0.globulin at PCA sites Bier col. In

progress.

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5.2 Brief description of research projects completed in 1966

5.2.1 Pemphigus foliaceus

Brazilian pemphiRus foliaceus or "fogo selvagem" constitutes

a sLgnificant public health problem in certain endemic foci of Brazil

where it occurs rather frequently, particularly among people of, the lower

socio-economic classes. Clinically and histologically, ,1.t is indistin-

guishable from pemphigus foliaceus as it has been described in North

America and Europe.

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............... However, the epidemiology.of -!fogo selvagem"' is clearly

different from pemphigus as it occurs elsewhere in the world (non-endemi.c

pemphigus).

Immunofluorescent studies of'Beutner and Jordon have " -

revealed the presence of autoantibodies to an intercellular component

of stratified squamous epithelium in' sera of active cases of non-endemic

pemphigus.

These observations (which have now been confirmed in a

number of laboratories) raised the question whether similar antibodies

would be found in Brazilian pemphigus. '. -

Preliminary studies revealed the same type of immuno-

fluorescent staining pattern with these sera as is demonstrable in non-

endemic pemphigus.'"'--Indeed, they were' found in high titers, often with

striking prozones.

The titer of intercellular antibodies has been found to

be proportional to the severity of the disease process in the non-endemic

forms of pemphigus... Therefore, a study was undertaken to determine

whether a similar relationship would hold in "fogo selvagemr".

Twenty-seven sera of patients with.Brazilian pemphigus '-e

were titrated for intercellular antibodies both in the.. Department of

Bacteriology and Immunology, School of Medicine, SUNY at Buffalo and in

Sao Paulo PAHO/WHO Immunology Research and Training Center. Twenty-two

sera showed positive results and titeras. found in the.two laboratories

were either the same or differed only by a factor of 2 (with one except:ion '

in which the difference was 4-fold).

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After titrations were completed, the sera were decoded

and a table was drawn up relating the severity of the disease to the titer

of intercellular antibody.

As in non-endemic pemphigus, a high correlation between the

two parameters was observed in the case of "fogo selvagem" (Table 4).

TABLE 4 RELATIONSHIP OF SEVERITY OF 'tOGO SELVAGEM'" TO THE TITER OF

INTERCELLULAR ANTIBODY AS REVFALED BY INDiRECT IEMUNOFLUORESCENT

STAINING.

JClinical Evaluation 1NQ ofTiters of intercellular antibody

cases

2560 1250i 640 532io 150 80 to lO 10

eteriorating 2 2

Stationary 13 2 6 4 1*

Improved 3 2 3

Remission 2 1

* This serum could not be titrated properly and exhibited variableresults on repeated tests (from less than 1/10 to 1/160).

The observations herein reported are preliminary and many

aspects of the problem have to be further investigated. It is apparent,

however, that immunofluorescence provides a useful tool in immuno-

pathologic and diagnostic studies of pemphigus foliaceus.

5.2.2 Characterization of enzymes in Bothrops venom

By using immunoelectrophoretic analysis followed by

specific staining, as described by Uriel and Avrameas (1965), tests were

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performed with the venom of Bothrops .iararaca in relation to 13 differentl

enzymes; 1-aminoacid oxidase, chymotrypsin, trypsin, protease, leucine

aminopeptidase, amylase, galactosidase, glucoronidase, alkaline and

acid phosphatases, cholinesterase, peroxidase and catalase. Positive

results were observed in relation to 4 of above mentioned enzymes, the

strongest reactions being those corresponding to chymotrypsin and 1-

aminoacid oxidase.

By combined use of Sephadex G-200, CM and DEAE-cellulose the last

mentioned enzymes could be obtained in separate fractions. The comparison

of immunoelectrophoretic slides stained for protein (amido black or light

green) and for specific substrates (acetyl-dl-phenylalanine naphtyl ester

for chymotrypsin; 1-tyrosin with addition of MMT tetrazolium salt and

phenazine methosulfate for 1-aminoacid oxidase) showed that chymotrypsin

activity was associated with precipitation lines obtained with commercial

Bothrops antivenom (Butantan Institute), whereas spot corresponding

to aminoacid oxidase did not correspond to a precipitation line.

* .

6. Teaching program planned for 1967 -

6.1 Visiting Professors

In 1967 the course will have the collaboration of 3 visiting . ·

professors:

Dr. E. H. Beutner Department of Bacteriology and ImmunologyState University of New York, Buffalo, " sU.S.A., from May 1-31.

Dr. B. H. Waksman Department of Microbiology, Yale Universi-ty, New Haven, U.S.A., from July 15 toAugust 15. . ..

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Dr. R. Binaghi College de France, Paris, France, fromJuly 1 to November 30.

The subjects to be developed by each visiting professor are

specified in Table 5.

6.2 List of Students

Eight students have been admitted in 1967:

Francisco Braga Andrade, M.D.

-Miguel Medeiros Montaña, M.D.

Maria Brazil Esteve, M.D.

Luis Sebastiao Prigenzi, M.D.

Helcio Corti Passos, Biologist

Paulo Guilherme Leser, M.D.

Ennio Avelar Naves, M.Do

Mitsuko Akashi, Biologist

Assistant-Professor of Microbiology,School of Medicine, University of Ceara,Brazil

Assistant-Professor of Microbiology,School of Pharmacy and Biochemistry,University of Rio Grande do Sul, Brazil.

Assistant, Immunology Department,Biological Institute, Sao Paulo.

Department of Microbiology and Para-sitology, Escola Paulista de Medicina,Sao Paulo.

Department of Microbiology and Para-sitology, Escola Paulista de MedicinaSao Paulo

Department of Medicine, Escola Paulista deMedicina, Sao Paulo

Department of Microbiology, Faculty ofMedicine, University of Minas Gerais,Braízl

Faculty of Philosophy, Sciences, andLetters, Itu, Sao Paulo.

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6.3 Teaching program

Table 5 gives the schedule of the teaching program planned for

1967. Experience acquired during the 1966 course showed that it is pos-

sible to.reduce the period of training to only 7 months (March to December) _

by eliminating the two periods of vacation allowed in 1966. The first month

of the course was devoted to the study of the fundamental bases of physico-

chemical methods in current use in immunology, as well as to a condensed

presentation of basic immunology following the topics suggested by a WHO

group of experts on the teaching of immunology for medical students (Annex 1).

TABLE 5 TEACHING PROGRAM FOR THE 1967 COURSE '~

Date Lectures Laboratory work

April 1-30 Introductory lectures pH determination. Buffers and indica-on basic immunology. tors.

Physical and chemical Visible light and UV spectrophotometry. ,methods of current use Column chromatographyo Gel-filtration.in immunology. Fractionation of serum proteins.

Estimation of proteins by UV spectro- -eDrsa. O. Bier, A.C.M. photometry, biuret and Folin-CiocalteuPaiva and EoL. Pradoo reagents. Micro-Kjeldahl.

May 1-31 Immunofluorescence: Titration of antibody by gel-precipita-principles. Quan- tion.titative studies. Fluorescent labelling. Characteriza- _

tion and atandardization of labelledApplications. antibodies.

Quantitation of IF staining.Dr. E. Ho. Beutner. Demonstration of nuclear antibodies.

Demonstration of antibodies to Strejp-tococcus and Treponema pallidun.Special projects.

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TABLE 5, conto

Date Lectures Laboratory work

June 1-30 The precipitin reaction. Quantitative estimation of antibodyComplement and complement by the Heidelberger and Kendallfixation. method.

Optimal proportion methods. Ramonfloculation.In vivo titration of antitoxino

Drs. 0. Bier and M. Quantitative C' fixation by theSiqueira. macro-method of Mayer et alo and by

the micromethod of Levine.Special projectso

July 1-15 Immediate hypersensiti- Systemic anaphylaxis, PCA and RPCAvityo in the guinea pig and in the rat°

Anaphilaxis in vitro: Dale test,degranulation of mastocytes.

Drso Ro Binaghi and M. Passive Arthus, direct and reverse.Siqueira. Biological properties of aggregated

gammaglobulin.Special projects.

July 16-31 Lymphoid organs and their Histology of lymphoid organs andrelationship to the immune characterization of immunocompetentresponse and to tolerance. cells.

Passive transfer of DH.Delayed hipersensitivity° Inhibition of macrophage migration.

Comparative histopathology of ArthusDr° Bo H. Waksman, and DH reaction.

Special projects.

August 1-15 Transplantation immunity. Histopathology of the homograftrejection.

Dr. B. Ho Waksman. Graft vs host reaction.Special projects.

August 15 - Immunochemical analysis Immunoelectrophoresis of normal andSeptember 17 by gel-precipitation. pathological sera.

Antigenic analysis in OuchterlonyDr. R. Binaghio plate.

Special projects._iiii iiiiti, .i

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TABLE 5, cont.

Date Lectures Laboratory work

September -.Protein chemistry. Immunoelectrophoretic characteriza-- r15-30 Enzymes. - tion of enzymes.

Drs. J. L. Prado and Special projecta.R. Binaghi.

October Immunoglobulins, structure Isolation of IgG, IgA, and IgM frora1-31 and biological activities. human serum.

Allotypes. ' Separation of gamma-1 and gamma-2Rheumatoid factors and guinea pig serum.other anti-gammaglobulin Enzymatic splitting and reduction ofantibodies. Ig. Carbohydrate content and anti-

genic determinants of fragments and zDr. R. Binaghi. chains .

Heterogeneity of Ig: starch-gél elec-trophoresis of isolated chains.Special projectso

November The production of anti- Antibody formation by isolated cells:1-15- bodies.- the plate and the "rosette" methods.

Immunotolerance. Titration of thyroid antibodies.Autoantibodies and disease.Special projects.

Drsa. R..Binaghi, 0. Bier,and N. Marques de Castro. ;

November Inhibition reactions, Measurement of hapten-binding by16-30 Equilibrium dialysis. equilibrium dialysiso .

Antigenicity and immuno- Preparation of azo and DNP-proteins.genicityo Inhibition reactions with sugars.

Passive hemagglutination. oDrs. R. Binaghi and M. The Coombs test.Siqueira. Special projects.

December Radioactivity methods in Estimation of antibodies (non-preci-1-15 Immunology. The ABC -pitating) by the ABC method.

method for antibody es- Clearance of labelled (I131) antigen t _timation. Radioimmuno- - from the blood of rabbit.diffusion. Blood clearance of carbon particlesMeasurement of RES acti-~ in the mouse.vity. Quantitative estimation of opsonins.Opsonins. Titration of insulin antibodies.

Special projects.Drso O. Bier and HoCorti Passos.

December 16-31 Final Examinations, Conclusion of special project;. t

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7. Final comments

The effort of PAHO/WHO in establishing immunology research and

training centers in developing countries represents an important step to-

wards the implantation of post-graduate teaching in these countries, as well

as for the training of the researchers needed for the specific problems of

such regions, particularly those related to the immunology of parasitic and

other tropical diseases.

As far as post-graduate teaching is concerned, the scheme of a 7

months course adopted by the Sao Paulo Center permits a selection of students

who, through a renewal of grants, could continue their studies and accumulate

additional credits in order to acquire either a M.S. or a PhoDo degree in im-

munology.

The experience of the Center in regard to the benefits brought by

visiting professors leads to a justifiable optimism in relation to PAHO/WHO

basic philosophy of polarizing the interest of outstanding immunologists in

the solution of practical problems related to the immunopathogenesis and to

the immunoprophylaxis of diseases which are rare or non-existent in developed

countries.

Finally, the establishment of local training centers certainly

represents an important measure to avoid the migration of scientists which

has been of main concern on the part of the PAHO/ACMR*o

* Pan American Health Organization, RES 5/10 and 5/lOa, Fifth Meeting ofACMR, June 1966.

r7

PAHO/WHO IMMUNOIOGY RESEARCH AND TRAINING CENTER

IN BRAZIL

0^~~~~ ~~ANNEX 1RES 6/15

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TOPICS FOR A MINIMAL COURSE ON BASIC IMMUNOLOGY

IN THE MEDICAL CURRICULUM

According to a Report of a WHO Expert Committee, 1966

(A.D.Addo, USSR; OoBier, Brazil; SoBoyden, Australia;R.R.A.Coombs, England; J.J.,ovan Loghem, NetherlandsR.J.Pautrizel, France; B.H.Waksman, USA; R.Go White ,

Scotland)o

TOPIC I

Problem of disposal of unwanted foreign and effete material.

Role of cells in this process in invertebrates. Phylogenetic development

of immunological competence for performing this task. Brief description

of basic phenomena, including non-specific mechanisms of uptake of foreign

material by phagocytic cellso Development of antibodies, delayed hyper-

sensitivity and graft rejection. Relation of these phenomena to resistance

to infection and to production of allergy and tissue damage° Concepts

of specificity and distinctions between self and non-selfo

TOPIC II

Biology of immune response. Procedures for producing an immuno-

logical response. Immunological memory and toleranceo Nature of gamma

RES 6/15Annex 1

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globulin and of specific antibody. Concepts of heterogeneity and classifi-

cation of immunoglobulinso Relation of structure of immunoglobulin molecule

to function. .

TOPIC III

Nature of antigen-determinant groupso Molecular requirements

for antigen and immunogenicity. Concept of hapten. and non-specific carrier°

Adjuvants. Antigen-antibody reaction° Optimal proportions° Primary and

secondary stages of reaction. Effect of electrolyteso Manifestations of

antigen-antibody reactions, including agglutination, precipitation, hemolys:is

and complement.fixation -

TOPIC IV

Cellular mechanisms of antibody production. Role of macrophage, -

lymphocyte and plasma cello Sites of synthesis of immunoglobulinso Anti-

body production as a specific example of protein synthesis. Agamma- .

globulinaemia. Multiple myeloma and macroglobulinemia. Autoimmunizationo

TOPIC V

Role of the lymphoid organs, including experimental studies of the

thymus and bursa of Fabricius. Immunological tolerance and paralysis. -t

Non-specific depression of immuLe response by X-ray and drugs. '$.

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TOPIC VI

Hypersensitivity reactions dependent upon humoral antibody° Ana-

phylaxis. Role of antigen-antibody complexes in production of Arthus

phenomenon and serum sickness. Atopy -Correlation of immunoglobulin

classes (reagins) with phenomena of hypersensitivity°

TOPIC VII

Delayed hypersensitivity. Role in experimental models of auto-

immune diseaseo Role in infectious granulomas, contact dermatitiso Diag-

nostic value of delayed hypersensitivity as in tuberculin testo

TOPIC VIII

Graft rejection. Induction of specific immunological tolerance°

Graft-versus-host reactions. Chimerism. Role of thymectomy. Tissue

transplantation in human as exemplified by skin, kidney and corneal graft°

TOPIC IX

Iso-immunizationo Blood transfusion° Erythrocyte, leucocyte,

platelet and transplantation antigena. Allotypyo Iso-antibodies.

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TOPIC X

Innate and acquired immunity. Organization of phagocytes (reticulo- 't

endothelial system) in relation to blood and lymphatic system. Mobilization

of granulocytes and macrophages in inflammation° Chemotaxis. Protective -,

effects of antibody. Principles of immunoprophylaxis. Active and passive

immunity against infective disease. Role of antibody as antitoxin, opsonin

and for neutralization of infection by viruses° Use of human and animal gamma-

globulins. Immunological response of infant and child. Transmission of

antibody across placenta and into milk and other body fluids. Dangers

attending serum therapy°

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