T. Mukuta et al., THYROID XENOGRAFTS FROM PATIENTS WITH GRAVES-DISEASE IN SEVERE COMBINED IMMUNODEFICIENT MICE AND NIH-BEIGE-NUDE-XID MICE, Clinical and investigative medicine, 20(1), 1997, pp. 5-15
Objective: To compare human thyroid xenografts from patients with Grav
es' disease in severe combined immunodeficient (SCID) mice and triple
immunodeficient NIH-beige-nude-xid (NIH-3) mice to obtain an improved
animal model for studying these xenografts. Design: Animal study. Part
icipants and animals: Patients with Graves' disease; SCID and NIH-3 mi
ce. Interventions: Thyroid tissue from six patients with Graves' disea
se was xenografted to SCID and NIH-3 mice; in addition, peripheral blo
od mononuclear cells (PBMC) from 12 patients with Graves' disease were
grafted intraperitoneally to separate SCID and NIH-3 mice. Outcome me
asures: Levels of human immunoglobulin (IgG), thyroperoxidase antibodi
es (TPO-Ab), thyroglobulin (Tg-Ab), and expression of thyrocyte interc
ellular adhesion molecule-1 (ICAM-1) and histocompatibility leukocyte
antigen (HLA-DR) in mice after xenografting. Results: IgG was detected
in all mice grafted with Graves' thyroid tissue and some mice grafted
with PBMC; levels of human IgG peaked 6 to 10 weeks after xenograftin
g. Human IgG levels reached a mean of 500 mg/L (standard error of the
mean [SEM] 150 mg/L) in the NIH-3 mice with thyroid xenografts. This w
as similar to results in SCID mice with thyroid xenografts, which had
a mean level of human IgG of 640 mg/L (SEM 230 mg/L). PBMC xenograftin
g resulted in a mean IgG level of 1200 mg/L (SEM 250 mg/L) in NIH-3 mi
ce, which was similar to the mean level of 1000 mg/L (SEM 280 mg/L) in
SCID mice. The rate of rise in human IgG in the sera of the NIH-3 mic
e with thyroid xenografts was similar to that in the SCID mice. TPO-Ab
were also detected in some mice with Graves' thyroid grafts and in a
few mice injected with PBMC, with levels peaking 4 to 6 weeks after xe
nografting. TPO-Ab levels reached a mean 109.3 U/mL (SEM 57.2 U/mL) in
the NIH mice with thyroid xenografts, which were similar to the mean
level of 91.7 U/mL (SEM 34.2 U/mL) in the SCID mice. There were no sig
nificant differences in the Tg-Ab levels in each type of mice (13.9 [S
EM 12.1] U/mL v. 17.9 [SEM 7.9] U/mL). Eight weeks after xenografting
into mice, the expression of xenograft thyrocyte ICAM-1 decreased sign
ificantly in both the SCID and NIH-3 mice (from 43.4%, SEM 4.9%, to 35
.9%, SEM 4.6%, in the NIH-3 mice, p < 0.05, and from 43.4%, SEM 4.9%,
to 32.5%, SEM 5.2%, in the the SCID mice, p < 0.05). However, the expr
ession of thyrocyte HLA-DR did not change significantly in the NIH-3 m
ice (from 11.5%, SEM 3.3%, to 10.8%, SEM 3.3%), whereas it decreased s
ignificantly in the SCID mice (from 11.5%, SEM 3.3%, to 4.2%, SEM 2.0%
, p < 0.02). Conclusions: Not only SCID mice but also NIH-3 mice may b
e useful as animal models for xenografted thyroid tissue, which will h
elp us elucidate the pathogenesis of autoimmune thyroid disease. NIH-3
mice are superior to SCID mice in maintaining the expression of thyro
cyte HLA-DR in Graves' thyroid xenografts at levels as high as those b
efore xenografting; this maintenance of expression may be due to the l
ack of natural killer cells in NIH-3 mice.