Recent developments in immunopharmacology

l?ecentdevelopments in immu opharma ology

Peter W. Mullen Kmic

Biwmarrh

Labow~vnm Ltd. Indtmiul MuII. P.O. Ban 878, KmtviUe.Now Smtia, CanoakB4N

4li8

study of the effecti of drugs on the immune system. The desire to understand the and to be recognized per se during the immunologi~l mechanisms of action (and seventies. At least two general texts interaction) of the many endogenous sub-

‘The nterdisciplinary biomedical science of imm~nopha~acolo~ began to take shape

twarmg the title Immunophunnocology have already been published”” and a third

bool, entitled Drugs and Immune Responf 978 U.K. Biological Couxil sym~um,a~~ared in iate I Y79. In addition, 1980 will see the publication of the second volume of THREE immunopharmacolog~ journals (fmmunophatmacology, the lnremational Journal of

sivcnPss”. based on a

immunophurmacoiogy

and the Journal of

published by El~vier~o~h-Holland. Pergamon and Marcel Dekker, respectively). each competcag for the sicadg stream of scientific papers emanating from this important sphere of research. Recent developments and trends in immunopharmacological research were ~g~i~ted this summer ~Br~hton. 29 July-l August} durinp the Fin t International Conference on Imrnunopharmacology. CIbviously, there is currently much interest in immunopharmacology although, in faa, it has long been recognized that the parent diiplines. immunolo~ and pharmacology. share certain research areas in common. This beilng the case, therefore, the reader might wish to pose two fun-

Pmmunophamzac&gy

stances - thymic hormones. lymphokines. chemotactic factors, prostaglandins and the cyclic nucleotides - constitutes the rationale behind much research in this area. The ultimate aim of immunopharmacological research. however. is the development of the chemical wherewithal to selectively control the immune system, particularly the malfunctioning immune system characteristic of a large number of disease states inchIding myasthenia gravis, asthma. ~eurnat~~id diseases and cancer. plus of course. the distinct but rarer immunodeficiency disorders themselves (e.g. Bruton’s agammaglobulinaemia and the Wiskett-Aldrich syndrome). Stud& of the possible insidious effects of drugs on the body’s immune respon-

siveness and the more blatant problem of drug allergies are other aspects of immunopharmacology. Recent evidence suggests that numerous drugs ranging from phenytoin’O to cannabis” can alter certain immune functions. it is essential. in this

regard, eventually to determine whether subtle. but detrimental, immunological effects can result from long-term treatment with all drigs in wide therapeutic use. damental questions: This increasingly important area of (i) What, exactly. should be understood immunopharmaculogy, broadened to by ihe term ‘immui!loph~acology’? and, include the myriad non-drug chemicals I ii) Why was it ody in the past decadeor (xcnobioti~) to which modem man is so that i~unop~l~acolo~ began to exposed, is best termed ‘immunotoxicol-

emerge as a distinct s&speciality? As a means of introducing the reader to the real,n of immunopharmacology, the presc:nt article will beqin with an attempt to imswer these two questions. 9* A look through the chapters of Ref. 7 should be sufficient to impress upon even the cursory reader that immunopharmacology is concerned with more than the ‘~~~~~~1~ Wltat&~

Ogy’.

although not well understood. a :ypc of ‘immune-drug’ interactLo is conceivable at the pharmacokinctic level when one considers that the body’s biotransformation capacity or ability to metabolize drugs may be decreased after treatment with agents (i~luding BCG and interferon inducers) that enhance the immune responseIs.

Why has immunopharmiwology only reeenrly been reeognkd as 8 dktinct t+u@e&&ty? frt view of the known overlap between immunology and pharmacologv in such areas as allergy and anaphylax-is.it may seem remarkable that immunopharmacology was so late in gaining the recognition and status of a distinct interdisciplinary subject. However. one must renlember that it is only reiatively recently that immunology has come into its own. To quote Sir Peter Mcdawar:

. until the mid-1930s or thereabouts. immunology was treated as an appendage to bacteriology from the point of view of research. teaching and university administration. Immunologv was therefore confined to its immelbiate practical applications: it was a matter of vaccines, skin tests. diagnostic antisera. blood groups. allergic reactions and not much else. It had indeed every imaginable shortcoming of an ‘applied science’ pursued without regard to its deep theoretical foundations. A new era began when chemists. zoologists and geneticists started to build up an entirely nek+conceptual structufr’ for immunology , .‘l. It seems reasonable to assume that the development of immunopha~acology was dependent in turn upon the full and separate development of immunology itself. Developments in immunopharmac&gy Kmmunopharm~cology has an immense scope and by way of introduction. some recent development and findings in this area have been selected for brief outline u:lder the following somewhat arbitrary subheadings.

In addition to the effects of drugs on the immune response, immunopharmacology is also concerned with the prospect of Autonomic agonists and cyclic nuclrotides immunol~l m~fi~tion of drug A consi~rablr! body of literature has action. The possibilityof attenuating drug accumulated in recent years which prooverdosageor perhaps, in certain diseases, vides evidence for a possible role of the reducing the effects of excessive product- autonomic nerv3us system in certain ion of certain endogenous hormones and immune responses. Both in vitro and in neurotransmitters usinl3specific antibodies viva, drugs such as the /I-adrenergic has immense potentiaP. Moreover, agonists, or other agents (e.g. theophyl-

TIPS -September,

IWO

353

lint) which cause an increase in intracellu-

ish Ihc immunocnhancing

lar cyclic AMP,

implications of such fmdings for dc>igning optimal combined immunotheraputic and

are known to have rnhibit-

ory effects on immune versely.

cholinergic

function(s).

agonists

which increase intracelkdar

Con-

(or

agents

cyclic GMP)

have a facilitatory or enhancing effect on the immune response. Such investigations of the effects of drugs on immune functicln in vivo and immunological have

been

tests in vitro

complemented

by

several

reports which amply dtmonstratc that different

populations

other

‘immunocytes’

receptors.

For

of

lymphocytes bear

instance.

specific in

and drug

humans,

it

appears that certain populations of both T and

B

lymphocytes

specific cellular

(responsible

immunity

for

and antibody

effect. The [rue

OH

.N

N

chemotherapeutic treatment schedules in cancer and other diseases remain to bc estimated. Some selectivity of immunosupprcsstve action has recently been reported for the lipophilic cyclic peptide cyclosporin A.

lymphocyte immune

subset which controls certain

responses by ‘suppressing’ other

lymphocytes)

may possess HI

histamine

receptrm?.

CH.

agents

3 CH.

recently

the complex

3

&.h

NH co

on on

&I.

This drug holds promise in transplantation

lsoprimmne

Furgcry since it appears to have little rnk
while

the inductive sponses to

preferentially

inhibiting

phase of T lymphocyte

CHZOH

re-

antigen. The immunopharmacology of this interesting compound has been reviewed in two previous issues of TIPS’.‘.

Immunoenhancing During munological

the

/

agents past

approach

decade to

an

cancer

on the concept of immunoll~pical

im-

-NH

CH, -C’-CO

A

based

-

CH -CO -NH-

CH

&I>

I

rurdell

CONH.

en. ZH. doo”

stimulatory’ agents. On the assumption that

Although long used therapeutically for their immunosuppressive action. it is only relatively

COOH

N

lance has precipitated a plethora of pamr\ reporting the use of varicqus ‘immuno-

Immunosuppressive

into

_

nocn, 0

production,

respectively) bear j5 adrenoceptors” while suppressor cells (a T

‘N

that some real insight immunological

mech-

anism$ of action of the corticosteroids and

a stimulated immune respoase will thv.art the development or progression of cancer. a number of immunoenharicing substances. ranging from whole bacteria (e.g.

drugs like cyclophosphamide has been gained. Although unrelated chemically and

Bacillus Calmette-Guerin (BCG) and Corynebacferium parvum) TV new drugs such as levamisole and isoprinosineX8. have

pharmacologically. both the corticosteroids’ and cyclophosphamide’@ are

been employed experimentall\ clinically in malignant disease.

known

Early enthusiasm over immunotherap! has waned somewhat with the realization

ion as an anthelmintic in \eterinan medicine. has several effrcrs on rhe deprcs-

mainly due to the loss of circulating young

that many immunotherapzutic approaches employing whole microorganisms tend io

lymphocytes since various studies have shown that plasma cells(the end-point of B

be only marginally beneficial to the cancer patient. Nevertheless. investigations along

sed immune system. Considering that it apparently restores malfunctioning phagoc~tr~ and T cells to normalit\. levamisolc IS brsr classified as an .a&-

to

affect

the

immune

system

similarly. Both agents cause a lymphopenia which. in the case of the corticosteroids’.

lymphocyte

development)

and

is

antigen-

and

causing sensifizarion ta tuberculin. Levamiwle (Fig. 1). th2 suhJrcr of much recent rttsearch since its original introduct-

these lines have increased tremendously

committed T and B ‘memory’ cells are little

our appreciation of the complex role of the

ancrgic’ or ‘thymomimetic’ cornPour& Isoprinosine is another agent (fig.

affected

variouscellular components of the immune response in cancer. It is nou believed rhar

u hich has a range of effects on thr immune response %‘. In addition fo antiviral proper-

(except

for

a

corticosteroid-

induced movement of these mature cells from the blood into various lymphoid tissues).

Of

course.

inflammatory steroids

the well-known

properties

result from

compounds

anti-

of the cortico-

the ability

of these

phages. Over the past few years rrsearch has Icd

of action of cyclophos-

to the development of chemically defined small molecules derived from bacterial cell

migration of phagocytic cells. phamide has been demonstrated findings which indicate ;mmunosuppressive

exert their anti-

and the

to retard chemotaxis

The complexity

many ‘immunostimulants’

cancer effects primarily by activating nonsuch as macrospecific ‘immunocytes’

by recent

that this ‘classic’

drug

can

actually

41s e;;zcts

which

have true

without

immunoadjuvant

the possible undesirable

effects (e.g. polyarthritis.

granuloma.

sen-

‘)

ties this agent is now knoun fo pnlmote thr, differentiation

of precursor ~211sto T I’m-

phoc+zs.Both isoprinosine and Irvamlsolr enhnnce the proliferative rrsponw elf human lymphocyte to mitngcns uithout possessing direct mitogenic activit? rhrmsrivrs. Mureovrr. both drugs can incrrasc the number of so-called ‘active’ human T I!mphocytes. With

the hwming

availability. ‘interferon’

prt>specf of ample

the rhrrapeutic pcrtenrial of has gained H i&spread pub

reac-

sltivity to endotoxin) associated with the use of whole organisms such as BCG. As a

tions, when given before the antigen“‘. In

result of Lederer’s pioneering work one of

Iicin

the most interesting of these compounds SO far isolated is muramyl dipeptide (X-

(viz. Time mapazinc. March) in recent months. Althtbugh of major interest to the

augment

certain immune

ticularly

delayed

responses. par-

hypersensitivity

mice, depending on the relative timing of its administration, cyclophosphamide (c. 100 mg kg-‘) appears to inhibit a suppres- acetylmuramyl-L-alanyl-D-isoglutamine)”. This substance (Fig. 1) represents the sor T cell population since the replenishment of treated animals with T cells minimal cell wall subunit constiruent which activity without obtained from untreated animals will abol- has immunocnhancing

through the scientific and Ia! prt’ss

immunopharmacologist. neither the interferon” ie nor thvmic hormone” star) can bc adequately

reviewed

here; the interrtsred

reader should see Refs Y. I 1 and

i6

354

conchldhlgeomments This article represents an attempt to introduce the ‘classical’ pha~acl~~ogist to the fast growing subject of immunopharmacology, including some recent drug developments in this area. With regard to the latter, however, it should be pointed out that, co~~side~ng the rna~~il~us eomplexity of the immune system. web simple

classifications as autontimic ttgents and cyclic nucieotides, immunosuppressive agents and immun~nh~nc~ng agents are quite a;bitrary. since, as mentioned earlier, immunasuppressive agents’ for example, may ~~ppear to be immunoenhancing depenrling upon numerous factors. temporal, :mrnuno~~~al and pha~a~logi~l in nature. Perhaps most drugs affecting the immune response should be labelled ‘immunomodulators’ to avoid az least some semantic prubIems. It is hoped that the fleeting taste of immunopharmacology offered by this article might encourage some readers to pursue for themselves a further awareness and understanding of this topical and intriguing interdisciplinary subject.

Reading Iht I l3014.1. F.

(lY80) 7iet1ds Phannn~&. &i. 1. l46-1,4Y 2 CahIc. R. Y. [ lY7Y) ~reff6i.t~~ton~~~. sci. I *

ht 1. htmunophar~

2,-7-1 -II.

3 4

5 6 7 8

9

10

1I 12

13 14

Cerufli. 1.. t%iny, C. and Schlumhcrger. 1. F. (lY7Y’) Int. 1. Itnmunophatma~d. I. W-63 Fauci. A. S. (197Y)J. Immunop!tarmoroL 1.1-2.5 Fineman. S. M,, Mudawwar, F. tf.a&Gehu. R. S. ( iY79) CullImmuml.4%12% 132 Fioersheim. G. L. (1979) in Drug and Immune Responsivenw (Turk. J. L. and Parker. D. cds). pp. l-24. MacMillan. London Hadden. J. W.. Coffey. R. G. and SpreafimxxF feds) (1977) Imrn~i~~~~~~. Plenum. New York Hadden. J. W.. Englnrd. A.. Sadlik. R. and Hadden. E. M. (1979) lnt. 1. Immunopharmacol. I. 17-27 Hartley. II?. F., W~no~~ka-Stewa~. M. and Stewart. W. E. II (1979) ht, J. fmmrtnophur??lacx?l. 1,.?19-226 Levo. Y.. Markwitz. 0. and TrainiF N. (1975) C&r. Exp. immunol. 19. S21-S27 Low.T. L. K ‘ and Goldstein. A. I. f 1979) Springer Semiin.Kvnimopathol. 2. 169-1 gf? Me&war. P. 8. and M&war, J. S. (1978) The Lik Science. Granada Publishing Ltd. St Albans. p. 98 Mullen. P W. ftY77) Br. 1. C&n. Pharmacol. 4. 69.S-698 Parant. hf.. Parent. F..Chcdid. L.. Yaps. A.. Petit.

Recent studies on anorectic a Silvio Garattini LkhaodiRinrcheF -bgiche‘Malio ;vpgn‘: Y&l Eheti,

62.20157

inttnduet&Jn Food intake is one of the activities that are indispensable for survival of the individual. The control of this important function is situate&in the central nervous systern, and the notion of defmed anatomical centers res~nsrble for hunger and satiety has persistedfor many years. Recent findings have. however, cast some doubts on this dogma,* and the spate of studies concerning the role of chemical transmitters in the brain has suggested that these may be impozIant in twang the peripheraI and/or centrai sij@s concerning the body’s nutritional status’. The search for drugs affecting food intake and particularly those reducing appetire (anor~ctic agents) has greatIy amtriiuted m our understand. ing of the me&&ms undexiyin& the control of food intake.. ~F&zkxr~~HOnRfilrro.dicJprnlySa

J. F. an’; Ledrrcr. E. (lY7Y) vwxvl. I. M-4 I

Miiatt, I&y.

Today two main classes of drugs are available to reduce appetite in man and as tools in experimental work. These are drugs &et require an intact Ca~choIamir~er~c system for their action (( +)-amphe:lamine, diethylpropion, phentermine and mazindol), and drugs thal require an intact serotoninergic system (fe~u~~ne. Qume, ~~hlorophenylpiperazine iliud MK 2 12). The chemical structures ot these compunds are given in Fig. 1. Tne classification above is based on the following criteria: (1) the drug must interact selectively with a giveln brain monoamine; and (2) manipulation of that monoamine shouid result in a change in the anoreetic effect of the drug. Irluftiple approaches are required to Qompettsate for the relatively poor specificity of the proce-

17 I’rucss. M. M. and Lcfknwt& S. S. (197X) Proc. Sot. t’xp, Eiol. Med. 1%. 3.50-X3 1X Ro~~lt~mlc. M. E, and ~nsinann. H. C. (cd.@ ( 197.5) Immwtt~pharmacok~gy. Spcctrm Pub. licatbns. Holliswuod. N. Y. I9 Shand. F. L. (1979) Int.1. Immuno4wmacol. i. 16_%5-171 2427-2428

Or peter W. Mu&n w&v5om in Nova Scotia where he completed his jint
pharnuztok~gy.Dr U&n mainLlLrsresearch hterexs in p~~c[Jk~pti~ Dand irnrn~o~~ii~&~g~ and he ‘I the fiunding edilcir of the International Journal of lmmunophannacu logy.

dures and drugs utilized as tools to manipu-

late bram monoamines. Newuche~

effect!5of ( + ~phetanline

and r&ted drugs It has been known fo- a long time that (+)-amphetamine Interacts with catecholamines. It mainly has an indirect ago&tic effect on noradrenaline and dopamine postsynaptic receptors, brought about by releasing these amines from the extragranular (reserpine-resistant) pool and by blo&ing the+ reuptake. That (-I-)amphetamine also affects dopamine metabolism is shown by a decrease of di-

oxyphenylacetic

acid, probably due to a

reversible intraneuronal blockade of monoamine-oxidase and to inhibition of

uptake of the released dopamine. and by an increase of 3-methoxytyramine and homovanillic acid. 1 shall not elaborate here on the wealth of data concerning the me~han~m of a&on of ( ~)-amphe~mine. Suffice it to say that the effect of (+)amphetamine on otecholamincs is remarkable because it has practically no effect on serotonin me?sboIism until very high concentrations are reached. Congeners of (+)-ampheta&ne such as phentermine and diethylpropion, or mazindol, a