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Pathogenesis of autoimmunity in New Zealand mice V. Loss of thymic suppressor function

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Pathogenesis of Autoimmunity in New Zealand Mice
V. Loss of Thymic Suppressor Function
Alfred D. Steinberg
Recent studies support the concept of thymic regulatory or suppressor
function. Such regulatory function appears to be present in the first
month of life in NZB and NZB/W mice, but is rapidly lost with age. Evidence is presented to support the hypothesis that loss of suppressor
function may play an important pathogenetic role in the development of
autoimmunity.
A major recent advance in immunology
has been the recognition that different
lymphoid cell populations interact in a
variety of immune responses. Such cellular
interaction was first demonstrated in humoral immunity when thymus and bone
marrow cells were found to cooperate positively in the antibody response to sheep
erythrocytes (1). Subsequently it was found
that two different subpopulations of thymus-derived (T) cells positively cooperate
in such cellular immune reactions as graftversus-host disease (GVH) (2) and skin allograft rejection (3).
In addition to positive cooperation evidence is accumulating to support the concept of negatively cooperating or suppressor
function. This has been studied most easily in the antibody response to antigens not
requiring thymic helper function. The antibody response to such an antigen, type
I11 pneumococcal polysaccharide (SSSIII),
was enhanced by the administration of anFrom the Arthritis and Rheumatism Branch, National Institutes of Arthritis, Metabolism, and Dimtive Diseases, Building 10. Room 8D19. National
institutes of Health, Bekesda, Maryland.20014.
Address reprint requests to Dr. Steinberg.
accepted
Submitted for publication June 18,197%;
September 5, 1973.
tithymocyte serum (ATS) (4), suggesting
that ATS eliminated thymic suppressor
cells. This was confirmed by the partial
suppression of the ATS-enhanced response
by the subsequent administration of thymocytes (5). Similar studies using other
antigens not requiring thymic helper function have also suggested the existence of
thymic suppressor function (6,7). Antibody
to thymic dependent antigens has in certain situations also been suppressed by
thymic regulatory cells (8-10).
In view of the finding that neonatal
thymectomy accelerated autoimmune disease in New Zealand mice (11) and that
thymus cells could retard antinuclear antibody production in strain A mice (12) my
colleagues and I undertook a series of
studies in an attempt to define the role of
thymic suppressor function in the pathogenesis of autoimmunity in New Zealand
mice. I will attempt herein to summarize
the evidence that New Zealand mice demonstrate an age-associated loss of thymic
suppressor function which correlates with
the
Of autoimmune disease'
One Of the hallmarks of autoimmune
disease in NZB/W mice is the spontaneous
development early in life of antibodies to
nucleic acids including double stranded
Arthritis and Rheumatism, Vol. 17, No. 1 (January-February 1974)
11
STEINBERG
RNA (13). Since the antibody response to
the double stranded RNA, polyinosinicpolycytidylic acid (poly I*poly C), has been
carefully described (14) a study of suppressor T-cell function was undertaken using
this nucleic acid antigen in female NZB/W
and control strain mice (7). It was found
that thymic helper cells were not necessary
for the antibody response to poly I*poly C.
Control BALB/c and BALB/c x DBA/2
(CDF,) mice demonstrated an enhanced
response to poly 1-poly C when given with
rabbit antimouse thymocyte serum (ATS),
whereas normal rabbit serum had no effect.
This suggested an elimination of suppressor cells as had been observed for SSSIII
(4). Furthermore, thymectomy led to an
enhanced antibody response to poly I*poly
C in BALB/c mice. Young NZB/W mice
aged 1-2 months also manifested an inhanced response to poly 1-poly C when
given with ATS. However 5- and 6-monthold NZB/W mice who were spontaneously
producing antinuclear antibodies no longer
responded to poly I*poly C and ATS (7).
This suggested that the thymic regulatory
control of nucleic acid antibody production is lost as NZB/W mice age.
T o determine whether or not the ageassociated loss of suppressor function was
restricted to antigens to which New Zealand mice spontaneously make antibodies,
the antibody response to SSSIII was studied
in female NZB mice (15). SSSIII was found
not to cross react with poly I*poly C. Antibody and antibody forming cells to SSSIII
were not spontaneously produced in detectable quantity in NZB mice between 1
and 10 months of age. When immunized
with the thymic-dependent antigen sheep
erythrocytes, the older NZB mice made
less antibody than did the younger NZB
mice. I n contrast, with increasing age NZB
mice, unlike BALB/c mice, responded to
immunization with SSSIII with progres12
sively higher antibody responses, suggesting a loss of suppressor function. This was
supported by the finding that thymus cells
from 1-month-old NZB mice significantly
reduced the excessive antibody response to
SSSIII of 10-month-old NZB mice. Twomonth-old thymus cells were not significantly effective, indicating a reduction in
thymic suppressor cells early in life. One
interpretation of the continued increase in
numbers of antibody forming cells through
6 months of age is that with the progressive loss of suppressor T-cells there was
continued expansion of the B-cell pool.
Studies with SSSIII suggested a general loss
of thymic suppressor function as New Zealand mice age.
A similar age-associated loss of suppressor function was demonstrated in a GVH
system (16). Twenty-five-week old NZB/W
spleen cells induced a more vigorous GVH
response in newborn C,H mice than did
6-week-old NZB/W spleen cells. This active
GVH response of 25-week-old spleen cells
was significantly reduced by small numbers
of spleen cells from 6-week-old NZB/W
mice, suggesting that suppressor function
in cell-mediated as well as humoral immunity is lost as New Zealand mice age
(16). The GVH activity of the 25-week
spleen cells was also significantly reduced
by small numbers of thymocytes from 1month-old NZB/W mice, demonstrating
that the young thymus has suppressor function for cell-mediated as well as humoral
immune functions.
The role of thymic suppressor function
in the autoimmune disease of NZB/W mice
was studied by techniques of thymectomy
and thymus grafting (17). Neonatal thymectomy led to accelerated autoimmune
disease, whereas thymectomy of 6- to 10week-old NZB/W mice did not. Thymuses
were next grafted from either 2-week-old
or 10-week-oldNZB/W mice into neonatal-
Arthritis and Rheumatism, Vol. 17, No. 1 (January-February 1974)
THYMIC SUPPRESSOR FUNCTION IN NEW ZEALAND MICE
ly thymectomized NZB/W mice. T h e 2week-old but not the 10-week-old thymus
grafts prevented the acceleration of autoimmune disease induced by neonatal thymectomy (17). This study may be interpreted as demonstrating that the %weekold NZB/W thymus possesses suppressor
function and that by 10 weeks of age this
function is lost. It suggested experiments
designed to restore suppressor function.
Perhaps the repeated administration of
young thymus grafts and cells might ameliorate the autoimmune disease. Recent attempts at such immunotherapy of NZB/W
mice have been complicated by both desirable and detrimental effects of repeated
thymic grafting. Nevertheless such grafting
has led to modest increases in survival in
animals receiving young thymus grafts and
cells (18).
The loss of thymic suppressor function
in New Zealand mice appears to take place
before other thymic functions are lost.
NZB and NZB/W mice 2 to 3 months of
age appear to have intact antibody responses to thymic dependent antigens and
their thymocytes can synergize with bone
marrow cells in an adoptive transfer system (19), suggesting intact helper T-cell
function in humoral immunity. Similarly
New Zealand mice of this age have intact
cellular immune capacities as measured by
induction of GVH disease (20) and skin
allograft rejection (3). It appears that New
Zealand mice 2-3 months of age have a
selective defect in a restricted thymic function-suppressor or regulatory functionrather than a generalized loss of thymic
function. Later in life other T-cell functions are lost (3.20,21) perhaps, in part,
caused by an antithymocyte antibody which
occurs in high titer in older New Zealand
mice (22).
Taken together the studies described
herein strongly suggest that New Zealand
mice lose thymic-suppressor cells as they
age, leading to hyperactive antibody responses including autoantibodies. In the
absence of normal thymic regulatory function B-cells may respond to self-antigens.
Preliminary studies suggest that suppressor
T-cells may inhibit B-cell proliferation
(7,23)T h e lack of T-cell suppression of Bcell proliferation might allow the magnitude of the autoantibody response to be
excessive. In the absence of suppressor cells
for both B- and T-cells, abnormal proliferation of lymphoid cells might progress
with age leading to lymphoid infiltration
of many organs, increased viral replication
(24), and ultimately lymphoreticular malignancy (25). Why suppressor cells are lost is
unknown. Such a loss might be caused by
either genetic or viral factors. Since there
appears to be thymus suppressor function
for both cellular and humoral immunity,
loss of suppressor T-cell function could be
involved in human autoimmune diseases
whether they be primarily humoral or cell
mediated. Better understanding of such
processes might lead to more specific immunotherapy.
1.
2.
3.
4.
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Arthritis and Rheumatism, Vol. 17, No. 1 (January-February 1974)
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14
Arthritis and Rheumatism, Vol. 17, No. 1 (January-February 1974)
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