!

"

!
!

$%
!

!
!

"#

!
"

"
!

$%

&'
)

( '
*

&

'% "
(

"

, "
+

!
)

.
/
1
"

'
0

1 "

"
"

2 - % $
%

'

%
$
3

$ !
" +
%

! +
$

.
/
" "

%
"%

6 '

7 8

"%

&
: &

)4
*
*

!+
+
5

) 9
& ;6

! %

'

+ )
,
&

"!
*

% !
" <

%
%

% !
"

+ )

Sustained IL-12 Signaling Is Required for Th1 Development

Veronica Athie-Morales, Hermelijn H. Smits, Doreen A. Cantrell, and
Catharien M. U. Hilkens
J Immunol 2004 172: 61-69.

"!

Effects of T Cell Frequency and Graft Size on Transplant Outcome in

Mice
Chunshui He, Soren Schenk, Qiwei Zhang, Anna Valujskikh, Jrg Bayer,
Robert L. Fairchild, and Peter S. Heeger
J Immunol 2004 172: 240-247

+ )
&

.=

/
%

,
-

- .
/ ,

/ %

&

+
,

/ ,

" <
0

1$
%

$> ! / %

+ ?

,
%
" -

!
"

" "
@A B #C B B $
" 0 %
3+
" >
"
" >2 %
%
! $+

)
/

$
!

"

Rat and Human Myelin Oligodendrocyte Glycoproteins InduceExperimental

Autoimmune Encephalomyelitis by Different Mechanisms in C57BL/6 Mice
Alfred R. Oliver, Geoffrey M. Lyon, and Nancy H. Ruddle
C57BL/6 mice immunized with the extracellular Ig-like domain of rat myelin oligodendrocyte
glycoprotein (MOG) developed experimental autoimmune encephalomyelitis (EAE) resembling that
induced by rodent MOG 35-55 in its B cell independence and predominantly mononuclear CNS infiltrate.
In contrast, human MOG protein-induced EAE was B cell dependent with polymorphonuclear leukocytes.
Human MOG differs from rat MOG at several residues, including a proline for serine substitution
atposition 42. Human MOG 35-55 was only weakly encephalitogenic, and a proline substitution in rat
MOG at position 42 severely attenuated its encephalitogenicity. However, human MOG 35-55 was
immunogenic, inducing proliferation and IFN-and IL-3 to human, but not rodent MOG 35-55. The B cell
dependence of EAE induced by human MOG protein was not due to a requirement for Ag presentation by
B cells, because spleen cells from B cell-deficient mice processed and presented human and rat
MOGproteins to T cells. The different pathogenic mechanisms of human and rat MOG proteins might
result from different Abs induced by these proteins. However, rat and human MOG proteins induced Abs
to mouse MOG that were equivalent in titer and IgG subclass. These data demonstrate that EAE can be
induced in C57BL/6 mice by two mechanisms, depending on the nature of theimmunogen: an
encephalitogenic T cell response to rat MOG or rodent MOG 35-55, or an encephalitogenic B cell
response toepitopes on human MOG protein that most likely cross-react with mouse determinants. The
Journal of Immunology, 2003, 171:462468.

"

Multiple Sclerosis with Uncommon Cerebrospinal Fluid Findings

Uro Rot, Anton Mesec, Tomaz Pogacnik
Department of Neurology, Medical Center, Ljubljana, Slovenia

Aim. To determine the frequency and clinical and laboratory features of patients with multiple sclerosis

characterized by uncommon cerebrospinal findings, ie, negative oligoclonal band or increased number of
mononuclear cells in cerebrospinal fluid.

Methods. The retrospective analysis included medical records of 233 patients (158 women and 75 men)

admitted to the Department of Neurology, Ljubljana Medical Center, between January 1, 1990, and
December 31, 1999 and discharged with the diagnosis of multiple sclerosis.Wedetermined clinical features
and cerebrospinal fluid parameters of patients with oligoclonal band-negativemultiple sclerosis and 15
mononuclear cells/mm3 in cerebrospinal fluid and compared them with patientswith oligoclonal bandpositivemultiple sclerosis and expected number ofmononuclear cells in cerebrospinal fluid, respectively.
There were 26 patients with oligoclonal band-negative finding and 26 with 15 mononuclear cells/mm3 in
cerebrospinal fluid. The two groups of patients did not overlap, except for one patient,who had 19
mononuclear cells/mm3 and was oligoclonal band-negative.

Results. The diagnosis was delayed in oligoclonal band-negative multiple sclerosis patients, their

cerebrospinal fluid contained less leukocytes, and lower concentration of IgG. The patients with _15
leukocytes/mm3 in cerebrospinal fluid were diagnosed earlier and had increased cerebrospinal fluid protein
and IgG concentrations.

Conclusion. Multiple sclerosis with negative oligoclonal band or increased count of leukocytes in cerebrospinal

fluidwere found in approximately 10% of patientswith the disease. Because of the absence of oligoclonal band and less
active cerebrospinal fluid, the diagnosis in these patients may be delayed.
Key words: cerebrospinal fluid; immunoglobulins; leukocytes, mononuclear; multiple sclerosis

&

%/

"

*
2

/-

& % "
1

.=

* $!
1$

%
! -

)
,0
!

2 "
"
1
>
2 "
%
2
!
!
%
"
+ !
D

$
>
"
5
$+ E

)0
" /
/

%
%

/
%

% -

>

)
$

'

" *
!

! 2
+

<%

"
!

2 "
D +
1
!

!
!
!

"!
$ 2

" +>
" +
<%
%
" 5

)
&
%/

.=

& % "

%
:

"

"

%
& "

"
"

" % "

%"
!%

"

<%

! !
%

% "

'

* +

'

,
%
! % $
1

!
"

<

"

!
1

<%

+ "
"

"

" ! %

'

* +

'

)
'

1
/

"

! "
!

$
% >

>!

#
!

+*$

"

" 0

%
"*! %

% F
>"

'

* +
&

%/

.=

1
"

'
.

"
"

# +
,0
!

! $
" <
! 02

2!
D 1
!
+
"

>
>*

*!
!

2 *

$!
5

!
! "
1

<%

" <
%
2

!
>

>!

"
+
> +E5
!

" %
"
""
5

2 5

# +

/
'

%
1

"

"E

"

%
%D 1
2

"
1

< %
%

1
!

">

Table 1. Clinical EAE in DA rats immunized with RSCH-PBS

Exp No

Incidencea

Day of onsetb

Mean max scorec

6/6

10.50.9

2.70.2

12/19

10.70.7

2.30.3

5/5

10.80.5

2.60.2

4/4

9.20.2

30

6/6

110.5

2.70.4

10/10

10.10.6

2.60.2

7/10

15.31

1.20.2

6/7

9.20.3

2.70.1

a Number

of rats with clinical signs of EAE/total number of rats

day S.E.M. when first signs of EAE appeared
c Mean maximal clinical score S.E.M. in diseased rats
b Mean

! !

" +

! G

! H

%
2 "
Fig. 1. IL-17 induces NO production in endothelial cells. Mouse VEC (1 x 105/well) were incubated
(A) with various concentrations of IL-17 for 72 h, or (B) or with IL-17 (50 ng/ml) for various time periods.
(C) Mouse VEC (1 x 105/well) were incubated for 48 h with or without IL-17 (50 ng/ml), in the absence
(control) or presence of IFN- (200 U/ml), and/or TNF- (100 U/ml). (D) Rat VEC (1 x 105/well) were
incubated for 48 hours with or without IL-17 (50 ng/ml) and/or IFN- (200 U/ml); *p < 0.05 refers to
corresponding cultures without IL-17.

# +
&

.=

+
!
1
!
%/

" <

" !%

"
"

$
1

$%

$!

1
>

*!
"

"

<
1

"

*
%
"

<%

$
+

%
%

"

!
&

% +

$
!

$ !

! $
!

$ !

+
"+

+
% 2

<
"

"

%
! <
/

/
F % "

"+ % /
%

! !
!

$! F

2
<%

% /
" <

!
%

<%

*
&
!

$%

.=

&

+
2

'% "

1
%
/

$
" %

'
% "
! %

% " !

&9
0

'

! %

Cell death is part of normal development and maturation cycle, and is the component of many response
patterns ofliving tissues to xenobiotic agents (i.e. micro organisms and chemicals) and to endogenous
modulations, such as inflammation and disturbed blood supply (1,2). Cell death is an important variable in
cancer development, cancer prevention and cancer therapy (3-5). In the treatment of cancer, the major
approach is the removal, by surgery, of the neoplasm and/or the induction of cell death in neoplastic cells
by radiation, toxic chemicals, antibodies and/or cells of the immune system (6-9).On the other hand, this
pathobiological process remains poorlyunderstood and the physiological and biochemical factorsthat lead
to cell death are still not clear... .......
&9
12 9 %

>
%

32
+ +
42
D
"%

0+
1

:>
E
G "

"2 :
+
5

" : +!
+

"
,

( 0M

"
"

( 0( +
*
+ @I0 J K L #J I L > C BB B 5
G> HG2
+
%

+G

+ 5:

>
# +
"
"M
+ 09
+
"
+
G
1 G5 9 + 2
@A 0 C OK I #C O I N > @L L O 5
>
#

8 >8
M0

"
1 + +
*1
2G N N0 @A AA #@A A I > C B B@5

"2

52 +
#:
> : * 2 > ) P #M
M
+ 8 >(
)>
* 8
"
2
AL 0 K O #K A > @L L J 5

"

*
"
2
"

"+ "
G ++
>
+

! G#& !G M >
+ 2

'

% " !

Although data on TNF levels in serum and CSF of MS patients are not consistent, a number of
reports demonstrated cytokine increase during the phases of disease activity (Spuler et al., 1996;
Drulovic et al., 1998) implying the significance of therapeutic approaches which would downregulate
TNF secretion or inactivate circulating TNF. However, a pilot study in two rapidly progressive MS
patients with a monoclonal anti-TNF antibody (cA2) unexpectedly revealed transiently increased
magnetic resonance imaging activity with the increase of cells and immunoglobulins in CSF and no
clinically significant neurologic changes (van Oosten et al., 1996). Furthermore, a phase III trial of
lenercept, another TNF inactivating agent was discontinued because of lack of efficacy (Weilbach
and Gold, 1999). It has been also shown that inhibitor of TNF synthesis, pentoxifylline lead to
worsening of the disease in 12 of the 14 MS patients while the production of TNF by monocytes was
reduced (Myers et al., 1998).
&9
Braun, N., Michel, U., Ernst, B.P., Metzner, R., Bitsch, A., Weber, F. and Rieckmann, R., Gene polymorphism at
position 308 of the tumor-necrosis-factor-
in multiple sclerosis and it's influence on the regulation of TNF-

production, Neurosci. Lett., 215 (1996) 75-78.

Drulovi , J., Mostarica Stojkovi , M., Levi , Z., Mesaro, ., Stojsavljevi , N., Popadi , D. and Pravica, V., Serum
interleukin-12 levels in patients with multiple sclerosis, Neurosci. Lett., 251 (1998) 129-132.
Ebers, G.C. and Sadovnick, A.D., The role of genetic factors in multiple sclerosis susceptibility, J. Neuroimmunol.,
54 (1994) 1-7.
Frei, K., Eugster, H-P., Bopst, M., Constantinescu, C.S., Lavi, E. and Fontana, A., Tumor necrosis factor and
lymphotoxin are not required for induction of acute experimental autoimmune encephalomyelitis, J. Exp. Med.,
185 (1997) 2177-2182.