he importance of ‘regional im-

munity’ was highlighted by a

comparison of how general im-

munological mechanisms were

modified for diffcrrnt lissurs such a5 the

eye and the skin (W. Streilein, Boston, MA).

The conjunctive, the intraocular eye and the

skin are equipped with indigenous antigen-

presenting cells (APCsI, afferent and rffer-

ent routes for communication with the im-

mune system, draining lymphoicl organs and

unique microenvironments created by their

constituent parenchymal ceils (Table 1). The

ocular surface konjunctiva) resembles (and

is in fact a component of) the mucosnl in-t-

mune system. Immune responses at this site

differ from both conventional skin immunity

and ocular immune privilege by emphasiz-

ing IgA antibodies as effector molecules.

General immunology of skin and

w= The type of immunity generated via the skin

is dominated by T cells that mediate de-

layed-type hypersensitivity (LITHI T helper

1 (Tl~lbtyx responses. By contrast, immun-

itv generated via tile eye leads to a deviant

immune response dominated by CDS’

T cells, often with a CD4’ Th2 component.

This aspect of ocular immune privilege has

been designated anterior-chamber-associ-

ated immune deviation CACAID) and de-

pends upon many unique ocular factors, in-

cluding constitutive intraocular expression

of Fas ligand IFa&), which may protnote

deletion of activated T cells in the eye’. Thl-

type skin immune responses can be modified

by changes to the cutaneous microenviron-

ment: for example, ultraviolet-l3 radiation in-

duces keratinocytes to produce factors such

as ris-uranic acid, tumor necrosis factor a

(TNF-4 and interleukin 10 f&IO) with the

abilitv to prevent cutaneous APCs from ac-

tivating naive T cells (1. Simon, Freiburg).

Similarly, ocular Th2-type responses and

ACAID can be abolished if ocular inflam-

mation is present at the time of antigen

administration into the eye’.

Maturation of skin dendrilic cells (I33

during culture is characlerized by d cessation

of major histocompatibility complex IMHCI

class 11 syntlwsis. However, in contrast to macropltage mnturc3 tion and activa tinn, the

expression of MHC class 11 in association

with antigal is stable and long-lived. A fur-

ther characteristic is the early expression of

accessorv molecules, which may be required

for initial nonspecific T-cell chlstcring lvith

APCs. The importance of CD&CD40 ligand

(CRLLOL) and Fas-FasL interactions during

this early phase of T-cell-APC interaction

was aiso emphasized’ and c!earlv has rele- i vance for intraoculLlr ACAlD mechanisms.

The role of t~tr;QceHular matrix ligands in ef-

fecting maturation was also highlighted in a

videotape analysis of DC motility in collagen

gels (E. K?impgec, Wiirzburg).

Ocular DCs occur in several different

sites including the c~~ijunctivvrt, the snterior

urea (iris/ciliary body), the posterior uvca

(chorotd) artd the orbital adncme CJ. Forrester,

Aberdeen). Conjunctival KS arc 111 many

ways similar to skin Langerlwns cells {LC’s)

and migrate lo the’ draining submandibular

and cervical lymph node when activated by

antigen {see Table 1). Intraocular DCs and/

or resident macrophages are presumed to

mediate ocular immune privilege via cyto-

kines such as transforming growth factor

p2 (TGF-P2). DCs in the posterior uveal

(choroidal) tract appear to be of two types

including a very large, tnntile veil-like cell

and rl smaller, migratory dendritiform cell.

ln addition, retin,ll pigment cpithclial (RPE)

cells modulate the function of choroidal

DCs depending on tile cocktail of cytokines

produced by resident cells. For example, in

response to IL-lp and TNF-a, RPE cells are

indtlccd to rclcnse graiiulocyt~2_macr(~pl~age

colony-slimulatil~g factor (GM-CSF) and

RANTES, which p remote APC clwmotaxis

and function, while in the presence of inter-

feron y (TFN-y) and TGF-P, tlw predominant

cytokine ruleasecl is IL-6 (Ref. 4.

There is IIO~Y accumulating evidence to sup-

port the cllncept of atopic dermatitis as a

paradigm cd an IgE-mediated DTH reac-

tion, \\*herr FceRI-expressing LCs represent

the pivotal Jsment (T. Siebcr, Munich)‘.

While nt~mal LCs qwess low amounts of

l&RI, the expression is strongly and specifi-

cally increased t ” Atopic dermatitis. Besides

the rcle<Isc of proinflammatory cytokines,

LCs use FceRI for antigen focusing for effi-

cicnt stimulation of T cells with minute

amounts nf allergens. Eosinophiis are also

believed to be of major importance as effec-

tor cells mediating the pathogenetically rel-

evant late-phase reaction, which is associ-

ated with a significant destruction of the

surrounding tissue in atopic dermatitis (A.

Kapp, HannoverIh. Toxic proteins that are

detected in this disease, such as eosinophil

c&ionic protein (ECP~, might play an im-

portant role by propagating the allergic in-

flammatory process and by modulating the

immune response. In addition, ECP levels

cumhtcd with ilw disease activity.

There are five allqic eye dlseascs: sea-

sonal allergic conjunctivitis, perennial aller-

gic conjunctivitis, giant papillary conjunc-

tivitis, vernal keratoconjunctivitis (VKC) and

atopic keratoconjunctivitis (AKC). VKC and

AKC are chronic, complex in mechanism,

and carry major blinding potential

ii,i 9 I ,’ -<- {‘l,,iy(,ji, >

IMMUNOLOGY TODAY

0X. Foster, Boston, MA). Like their derma-

tological counterparts, cells of an immediate

and a late-phase reaction are detectable,

While mast-cell mediators are important

contributors to the ocular damage, eviderze

now indicates that, in patients with VKC and

AKC, cytokines released from eosinophils in

the late phase catise damage to ocular cells

leading to cornea1 involvement. Although

mast-cell stabilizers represent an advance in

the development of drugs that can help pre-

vent blinding in VKC and AK (Ref. 7), more

attention to eosinophil modulation is clearly

needed. Cyclosporin A might be effective in

reducing the immunological damage, but its

effects are incomplete and are not uniform.

IL-13 and IL-4 are equally potent in

inducing IgE-synthesis (E. Wierenga,

Amsterdam). In contrast to Thl cells, Th2

celIs express a rather low killing capacity.

The secretory repertoire of APCs such as

monocytes and DCs might be crucial in

skewing the T-cell profile. Lipopolysac-

charide (LPS)-stimulated monocytes pro-

duce IL-12 within 8 h but prostaglandin E,

@‘GE,) is released after 24 h. IL-12 and PGE,

can direct the outcome of the differentiation

of naive T cells towards Thl and Th2 cells,

respectively. However, IL-12 can exacerbate

ongoing Th2 responses, so that its use in

therapy of allergic diseases is questionable

(I? Jeannin, Geneva). Similarly, there is some

evidence that strategies aimed at down-

regulating IgE synthesis by altering

CD4OXD40L interaction with recombinant

molecules lack promise. By contrast, some

hope could be invested in N-acetyl-cystein

(NAC), which is known to interfere with

apoptosis. Indeed, results b vitro suggest

that NAC decreases IL-4 production by

T cells and thereby inhibits the transcription

of mature IgE transcripts. Furthermore,

feeding rats with NAC strongly modulates

IgE synthesis in vivo.

!kcsicSosis

Besides lung infiltration, sarcoidosis can

lead to various forms of skin and eye mani-

festations. Cutaneous sarcoidosis has vari-

ous clinical appearances: for example, typi-

cal nodules and plaques, erythema nodosum

or the characteristic lupus pernio tK. Degitz,

Munich). Skin and ocular sarcoidosis

Ie I. erties of the skib an

Cornea and Skin Conjunctiva intraocular tissue

LCs {epidermis); LCS DCs, macrophages

None {cornea): DCs. macrophages

(dermis) (uveal tract)

Component

Local APCs

Homing CLA+; L-selectin’ Unknown Unknown _

Afferent route Lymphatics Lymphatics Aqueous drainage

via veins

Blaockissue barrier Fenestrated

Lymphoid organ Regionai lymph

node

Fenestrated Tight junctions

Regional lymph Spleen

node

Abbreviations: APCs, ant&en-presenting; cells; CLA, cutaneous lymphocyte antigen; DCs, dendritic cells; LCs, Langerhans cell;. _ ”

(uveitis) (M. Zierhut, Tiibingen) can mimic

various other disorders both clinically and

imrnunohistologically, raising the possibility

that sarcoidosis could be a more general

inflammatory response to several antigens.

No single suspected antigen seems to be re-

sponsible in the majority of cases, and re-

cent studies trying to identify mycobacterial

DNA by polymerase chain reaction in sarcoid

lesions have gtlderally been disappointing.

The characteristic lymphopenia in sar-

coidosis reflects a redistribution of lympho-

cytes to sites of inflammation. Depending

on the organ, the CD4:CDB ratio is elevated,

reaching 1O:l in the choroid of uveitis pa-

tients. Activated macrophages and Thl cells

are the predominant cells in the lesions. The

role of Thl and Th2 cells has been studied

exclusively in the lung (E. Fireman, Tel Aviv):

Th2 cells favor fibrosis whereas Thl cells

can lead to resolution. A low ratio of Thl :Th2

cells therefore carries a bad prognosis. In

the lung, an overexpression of T-cell recep-

tor (TCR) yl has been found, but T cells in

the lacrimal gland also show an abundance

of TCR variable (V)Sl, VS2, Vyl and Vy3

(Ref. 8). Therapy with IFNy, which shifts

the balance to Thl cells, has already shown

promising results in pulmonary disease, but

has not been used in ocular sarcoidosis.

Pigment cells and tumors of the skin and eye Pigment cells of the skin and eye can gener-

ate malignant neoplasms. However, the

behavior of melanomas that originate from

skin differs markedlv from that of ocular

melanomas. More importantly, the immune

system participates in the pathogenesis of

both types of melanomas, but in different

ways. Bv contrast to skin melanomas, OCU- i lar melanoma5 arise in ai immunologically

privileged site (B. Ksander, Boston, MA).

Although the primary ocular tumors grow

Slowly, more than 50% of patients develop

distant metastases (chiefly liver) for which

there is no cure”. However, since the intcr-

val between primarv and distant m&stases

is often verv Long, there is time for immune

intervention, such as the use of tumor-

specific vaccines. Experiments have been

aimed at creating such a vaccine by trans-

fecting 87 and IL-12 into tumor cells from

human primary ocular melanomaP. Trans-

fected cells readily activate tumor-specific,

HLA-restricted cytotoxic T cells. Moreover,

metastatic cells from ocular melanomas ex-

press abundant class 1 molecules, rendering

them susceptible to killer-cell lysis. Thus, the

potential exists that a vaccine derived from

primary ocular melanomas might induce im-

munity of a type able to prevent metastases

from estabiishing residence in distant organs.

In contrast to ocular melanoma, primary

cutaneous melanoma frequently undeigoes

partial regression, and is coms1~~11y infil-

trated by T cells and macrophages. k~-

ever, the paradox is the coexistence of mela-

noma-specific immunity IVitli mclanonia

pqyession. Several mechanisms have been

found in melanoma that explain its escape

from immune recognition and destruction

(E. Br&ker, W iirzburg) (reviewed in Ref. 11).

These include: genetic instability leading

to early antigenic heterogeneity; loss of ex-

pression of MHC class i antigen during local

and systemic progression; release of secre-

tory intercellular adhesion molecule 1

(sICAM-I ) by melanoma cells, thereby

blocking tumor-leukocyte interactions; pro-

duction of immunosuppressive cytokines

such as TGF-PI and IL-10 by melanoma

cells; and induction of anergy by melanoma

cells in CQ4’ autologous T cek’z.

These mechanisms should thus be the targets of immunotherapy in skin and eye

melanoma.

Conchding remarks By comparing the eye and the skin, this meet-

ing highlighted how tissues modulate the

immune response: immunological mecha-

nisms in allergic responses in the skin and

in the conjunctiva have many features in

common, mediated by similar populations

of APCs. By contrast, tumor reponses are

quite different, e.g. for skin and eye mda-

noma, in which ACAID appears to have a

major modulating effect. However, ACAID

might not be wholly protective for T-cell

mediated responses since conditions such as

systemic sarcoidosis can affect all ocular com-

ponents. Clearly, selective tissue immuno-

regulatory mechanisms can be bypassed

if the microenvironmental condition5 are

changed appropriately. Current research is

aimed at determining how these changes

are induced.

References

1 Griffith, T.S., Brunner, T., Fletcher, SM.,

Green, D-R. and Ferguson, T-A. (1995) Scieme

270,1189-1192

2 Streilein, J.W., Bradley, D., Sane Y. and

Sonoda, Y. (1996) hwst. Og~htl~dJ~20I. Vis. Sci. 37,

413-424

3 Ktimpgen, E., Gold, R., Egg&, A. et nl.

(1995) 1. Crll. BiocRrrli. CSuppl.) 21h, 12

4 Kuppner, MC., McKillop-Smith, S. and Forrester, J.V. (1995) Iwnr~rw~log!/ 84, 265-271

5 Bieber, T. Clrl-I. O@. Iwwtrr~oI. (in press)

6 Kapp, A. (1993) AIfqy 48, 1-5

7 Foster, C.S. and Calonge, M. (19901

Ophflinlw~oloS!/ 97, 992-1000

8 Smith, J.A.. Whitcup, S., Mahdi, R.M.,

Nussenblatt, R.B. and Egwuagu, C.E. (1995)

!JKkYf. Ophh~hJ~~. Vis. Pi. 36, 537

9 Zimmermann, L,E. and McLean, J.W. 11979)

AJII. 1. Ophtkahol. 87, 741

10 Ksander, B.R,, Rubsamen, I?, Olsen, K.,

Cousins, S.W. and Streilein, J.W. I19911 Iwest.

O,t~l~!l~r?lf?rol. Vis. 5-i. 32, 3198-3208

11 Riinger, T.M., Klein, CL, Becker, J.C. and

Brticker, E.B. (1994) C~,rr. Ollii~. O~~cu~. 6,

18% 1% 12 Becker, J.C., Brablctz,T., Conrad, C.T.,

BrGcker, E.B. and R&&Id, R.A. (1995) Proc.

Nntl. Ad. SC-i. U. S. A. 92, 2375-2378

Emmanna Ciccone, Carlo Enrico Grossi and Andrea Velardi

t has been shown recently that a

subset of CD3’CDS’ cytotoxic

T lymphocytes (CTLs) egress surface

.moIecules of the immunoglobulin

superfamily that function as receptors for

human major histocompatibility complex

[MHC) HLA class I alleles and exert in-

hibitory effects on cell-mediated cytoly-

sislW3. These receptors, which are typically

found on a large proportion of CD3- T-celi

receptor (TCR)- natural killer (NKl cellsJ,5,

have been tentatively termed kiIl?r-cell ir

hibitory receptors UURsY’, and can be sub-

divided into GL183 (Refs 1, 2) specific for

(see Table 1). In normal subjects, this CTL

subsrt accounts for less than 5% of the pti-

ripheral blood T cells, but it is expanded

considerably 040%) in the reconstitution

phase that follows bone marrow transplan-

tation (BMT) from three loci-incompatible

donors7. CTLs also express activatory TCRs

that are capable of triggering the cytolytic

program of these cells.

Thus, there is convincing evidence for

the existence of a subpopulation of CTLs

that express two distinct sets of receptors for

HLA class I molecules that mediate opposite

functions.

PII 10161.5699(96)30054.6