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(American Journal of Pathology. 2002;161:755-761.)
© 2002 American Society for Investigative Pathology

Short Communication

The Role of the Thymus in Development of Necrotizing Arteritis in Transgenic Rats Carrying the env-pX Gene of Human T-Cell Leukemia Virus Type-I

Kazunori Fugo, Akihiro Ishizu, Hitoshi Ikeda, Hiroko Hayase, Toshiaki Sugaya, Masato Higuchi, Muneharu Tsuji, Asami Abe, Akira Suzuki, Masahiko Shibata, Toshiyuki Takahashi and Takashi Yoshiki

From the Department of Pathology/Pathophysiology, Division of Pathophysiological Science, Hokkaido University Graduate School of Medicine, Sapporo, Japan


   Abstract
Top
 Abstract
Materials and Methods
 Results
 Discussion
 References
 
Necrotizing arteritis mimicking polyarteritis nodosa occurred in transgenic rats carrying the env-pX gene of human T-cell leukemia virus type I. To investigate the pathogenesis of necrotizing arteritis in these rats (env-pX rats), adoptive transfers of spleen cells and bone marrow cells were done from env-pX rats before they developed arteritis to nontransgenic rats. Necrotizing arteritis occurred in lethally irradiated nontransgenic rats reconstituted by env-pX spleen cells, thus indicating that the env-pX transgene in affected vessels may not be essential for the development of arteritis. In contrast, arteritis was not induced in nontransgenic recipients by adoptive transfers of env-pX bone marrow cells, which suggested that T cells derived from the env-pX thymus may play a role in the development of arteritis. To clarify if the process of differentiation of T cells in the env-pX thymus is crucial to develop necrotizing arteritis, reciprocal exchange of thymus frameworks was done between env-pX and nontransgenic rats. Necrotizing arteritis occurred in nontransgenic rats with an env-pX thymus framework, whereas development of arteritis was suppressed in env-pX rats in which the thymus framework was replaced with a nontransgenic one. This collective evidence shows that the thymus is directly associated with the development of necrotizing arteritis in env-pX rats.

Human T-cell leukemia virus type-I (HTLV-I) is associated with a number of diseases, including adult T cell leukemia,1,2 myelopathy,3,4 uveitis,5 and probably arthropathy,6 Sjögren’s syndrome,7 T cell alveolitis,7,8 and infective dermatitis.9 To investigate the pathogenetic role of HTLV-I in these diseases, we established and analyzed rat models for HTLV-I infection10-16 and transgenic rat lines carrying the env and/or pX genes of HTLV-I.17-21 In our previous work, the env-pX gene was introduced into the germline of Wistar-King-Aptekman-Hokudai (WKAH) rats under the control of the HTLV-I LTR promoter.18 The env-pX transgene was expressed constitutively in systemic organs of these rats (env-pX rats). Vasculitis and other collagen vascular diseases occurred in env-pX rats. Small- to medium-sized arteries in connective tissues around the thymus, salivary glands, testis, pancreas, and in the dermis, but never glomeruli or large vessels such as the aorta, were mainly affected. A cellular infiltrate containing lymphocytes, neutrophils, plasma cells, and histiocytes with proliferation of fibroblastic cells surrounding affected arteries was present, and fibrinoid necrosis was evident in the intima and/or media. These histological characteristics corresponding to necrotizing arteritis and the tissue distribution resemble findings in polyarteritis nodosa in humans. Because autoantibodies, including anti-nuclear and anti-DNA antibodies, were present in the sera, autoimmune phenomena may play a role in the pathogenesis.

To determine whether cellular autoimmune responses are involved in the pathogenesis of necrotizing arteritis in env-pX rats, adoptive transfers of spleen cells (SCs) and bone marrow cells (BMCs) were done from env-pX rats before they developed arteritis to lethally irradiated nontransgenic WKAH rats. We also examined reciprocal exchange of thymus frameworks between env-pX and WKAH rats to clarify roles of the thymus in the development of necrotizing arteritis in env-pX rats.


   Materials and Methods
Top
 Abstract
 Materials and Methods
Results
 Discussion
 References
 
Rats

Inbred WKAH rats and WKAH rats bearing the env-pX gene of HTLV-I (env-pX rats)18 were maintained at the Institute for Animal Experimentation, Hokkaido University Graduate School of Medicine. Experiments on animals were done in accordance with the Guide for the Care and Use of Laboratory Animals in Hokkaido University Graduate School of Medicine (http://www.hokudai.ac.jp/animal/houki/hokudaisisin.html).

Polymerase Chain Reaction (PCR) for the Transgene

Peripheral blood mononuclear cells were separated from total blood of rats, using Lympholyte Rat (Cedarlane, Ontario, Canada). The env-pX transgene in genomic DNA extracted from the peripheral blood mononuclear cells was amplified by PCR, as described.18

Cell Transfer Experiments

Mononuclear cells were separated from spleen and bone marrow, respectively, using Lympholyte Rat. Donor env-pX rats (male, 6 to 8 weeks of age) were confirmed microscopically to be disease-free. Nontransgenic WKAH rats (male, 6 weeks of age) were lethally irradiated at 12 Gy by 60Co and served as recipients. SCs or BMCs from env-pX rats were injected via the tail vein of lethally irradiated WKAH rats. Each recipient was given 1 x 107 SCs or BMCs from a single donor. Transfers from env-pX to env-pX and from WKAH to WKAH rats were made to serve as positive and negative controls, respectively.

Reciprocal Exchange of Thymus Frameworks—Thymectomy and Thymic Transplantation and BMC Transfer (Tx+TT+BMT)

Thymi from newborn env-pX rats were physically crushed to remove >90% of the thymocytes, then the residual thymic tissues were soaked in RPMI 1640 medium containing 1.5 mmol/L of 2-deoxyguanosine (Sigma, St. Louis, MO) for 7 days, as described by Martin-Fontecha and colleagues.22 After the deoxyguanosine treatment, histological examinations showed that the thymus frameworks remained intact and most of the residual thymocytes were critically damaged (data not shown). The thymus frameworks were implanted into the renal subcapsular space of WKAH rats (male, 6 weeks of age) that had been given lethal irradiation (12 Gy) followed by thymectomy. Then, hematopoietic cells of these rats were reconstituted by WKAH BMCs (1 x 107 BMCs from a single donor/recipient). A reverse combination of env-pX and WKAH rats was also done.

Analysis of the Implanted Thymus Framework

To examine reconstitution of the thymus, recipients were sacrificed 2 months after the Tx+TT+BMT. The kidney implanted with the thymus framework was sectioned and stained with hematoxylin and eosin (H&E). In addition, phenotype of lymphocytes in the reconstituted thymus was analyzed using flow cytometry. For this purpose, cells were stained with fluorescein isothiocyanate-labeled anti-rat CD4 and phycoerythrin-labeled anti-CD8 antibodies (Pharmingen, San Diego, CA).

Evaluation of Vascular Lesion

Six months after the cell transfer and Tx+TT+BMT experiments, recipients were sacrificed for pathological examinations. Systemic organs, including cerebrum, cerebellum, spinal cord, salivary glands, heart, lung, liver, kidney, adrenal glands, pancreas, intestine, testis, thymus, spleen, lymph nodes, ankle joints, muscle, and skin were sectioned and stained with H&E. Specimens with evident vascular lesions were further examined in elastica van Gieson, Masson trichrome, and phosphotungstic acid hematoxylin stainings, and in immunohistochemistry using anti-rat CD3 antibody (Cedarlane).

Laser-Capture Microdissection

From formalin-fixed paraffin-embedded sections (4 µm), 1 x 103 lymphocytes accumulating at the affected vessels were dissected using Laser Capture Microdissection LM2000 (Arcturus, Mountain View, CA). An equal number of env-pX lymph node cells were microdissected similarly and served as a positive control.

Nested PCR

DNA was extracted from the microdissected samples. To detect the pX gene, nested PCR was done using oligonucleotide primers, 5'-GCATGACACAGGCAAGCAT-3' (sense) and 5'-CCGAACATAGTCCCCCAGAGAT-3' (antisense) for outer primers (35 cycles), and 5'-CAGATACAAAGTTAACCATGCTTATTATCA-3' (sense) and 5'-ACACGTAGACTGGGTATCCGAAA-3' (antisense) for inner primers (40 cycles). The products were electrophoresed and analyzed using Bioanalyser (Agilent Technologies, Waldbronn, Germany).


   Results
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 Abstract
 Materials and Methods
 Results
Discussion
 References
 
Development of Necrotizing Arteritis in Lethally Irradiated WKAH Rats Reconstituted by env-pX SCs

Results of cell transfer experiments are summarized in Table 1 . Necrotizing arteritis was evident in three of nine lethally irradiated WKAH rats (33%) that underwent SC transfers from env-pX rats. The affected vessels included arterioles in the mediastinum and testicular arteries. The arteritis was of the necrotizing type and similar to naturally occurring arteritis in env-pX rats (Figure 1) . Additionally, the incidence of arteritis was equivalent to that in untreated env-pX rats (9 of 27, 33%).18 No evidence of arteritis was found in nine lethally irradiated WKAH rats that received env-pX BMCs.


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  		Table 1. Summary of Cell Transfer Experiments

 


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  		Figure 1. Necrotizing arteritis in lethally irradiated WKAH rats reconstituted by env-pX SCs. The affected vessels in these figures are the testicular artery (A–C: original magnifications, x100; D: immunostaining for CD3, original magnification, x400) and arterioles in the mediastinum (E and F: original magnifications, x200). A and E, H&E staining; B, elastica van Gieson staining (disruption of elastic fibers is evident); C and F, phosphotungstic acid hematoxylin staining (fibrinoid necrosis of the arterial wall is evident).

 
Immunohistochemical study revealed that the infiltrating cells included CD3+ T cells (Figure 1D) . SCs contain heterogeneous cell populations. Among them, one major population consists of T cells, and others of extrathymically derived cells, including B cells, plasma cells, macrophages, and dendritic cells. If these non-T cells play important roles in the pathogenesis in env-pX rats, necrotizing arteritis might also be induced in WKAH rats by adoptive transfer of env-pX BMCs. Thus, we considered the possibility that T cells may be mainly associated with env-pX arteritis. In addition, the majority of T cells in the env-pX SCs are mature after positive and negative selections in the env-pX thymus, while a portion of immature cells from the env-pX BMCs will differentiate to mature T cells in nontransgenic thymus of recipients after transfer into WKAH rats. Therefore, failure of proper differentiation of T cells in the env-pX thymus may possibly play a key role in the development of necrotizing arteritis in env-pX rats.

The Thymus Is Crucial for Necrotizing Arteritis to Occur in env-pX Rats

To clarify whether the env-pX thymus plays an essential role in the pathogenesis of necrotizing arteritis, reciprocal exchange of thymus frameworks (Tx+TT+BMT experiment) was done between env-pX and WKAH rats (see Materials and Methods). Two months after the Tx+TT+BMT, histological examination revealed that cortical and medullary structures of the thymus had been reconstituted in the renal subcapsular space where the thymus framework had been grafted (Figure 2A) . Because the majority of lymphocytes in this reconstituted thymus were positively stained for both CD4 and CD8 (Figure 2B) , the heterotopically grafted thymus framework was considered to be functioning in the recipients. When genomic DNA extracted from the peripheral blood mononuclear cells of recipient WKAH rats with an env-pX thymus graft was examined to identify contamination of env-pX lymphocytes derived from the implanted thymic tissue, the env-pX transgene was not detected by PCR (Figure 2C) . Thus, the level of contamination was considered to be below the sensitivity of our PCR (<1 env-pX lymphocyte per 104 normal lymphocytes).



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  		Figure 2. Tx+TT+BMT experiment. A: Reconstituted thymus in the renal subcapsular space (H&E staining; original magnification, x40). B: Flow cytometry of cells from the reconstituted thymus. C: Detection of the env gene in peripheral blood mononuclear cells by PCR. Genomic lck promoter region was also amplified to verify DNA extraction. Lane 1, 100-bp ladder marker; lane 2, sample from an env-pX rat as positive control; lane 3, sample from a WKAH rat in which the thymus framework was replaced with an env-pX one.

 
At 6 months after the Tx+TT+BMT, 4 of 11 WKAH rats (36%) with an implanted env-pX thymus framework showed evidence of development of necrotizing arteritis (Table 2) . Histopathological features and the incidence were similar to those of necrotizing arteritis seen both in env-pX rats and WKAH rats that received adoptive transfers of env-pX SCs (Figure 3) . The env-pX transgene was not detected in a DNA sample extracted from lymphocytes microdissected from the arteritis lesion by nested PCR (Figure 3D) . Arteritis never occurred in env-pX rats in which the thymus framework was replaced with a nontransgenic one.


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  		Table 2. Summary of Reciprocal Exchange of Thymus Frameworks

 


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  		Figure 3. Necrotizing arteritis in a WKAH rat with an env-pX thymus framework. The affected vessel in this figure is the testicular artery (original magnification, x200). A, H&E staining; B, elastica van Gieson staining [disruption of elastic fibers is evident (arrows)]; C, phosphotungstic acid hematoxylin staining [fibrinoid degeneration of the arterial wall is evident (arrow)]; D, detection of the pX gene in DNA extracted from microdissected samples by nested PCR. Lane 1, ladder marker; lane 2, sample from env-pX lymph node cells as positive control; lane 3, sample from lymphocytes accumulating at the arteritis lesion in a WKAH rat with an env-pX thymus framework. An expected molecular size of the nested PCR product is 90 bp.

 

   Discussion
Top
 Abstract
 Materials and Methods
 Results
 Discussion
References
 
Vasculitides in humans vary in pathological characteristics, suggesting that diverse etiologies may be implicated in the syndromes.23 Analysis of animal models facilitates understanding of the pathogenesis. F1 mice of New Zealand Black and White strains (NZBxNZW F1) develop glomerulonephritis at a high frequency and also necrotizing arteritis albeit with a lower frequency.24 Because deposition of immune complexes and complements is evident in affected glomeruli and vessels, humoral immune responses play direct and crucial roles in the pathogenesis. NZBxNZW F1 mice are regarded as being a good model for glomerulonephritis and necrotizing arteritis related to systemic lupus erythematosus in humans. On the other hand, deposition of neither immunoglobulins nor complements in affected vessels may be evident in some cases of vasculitis, including polyarteritis nodosa, hence other factors than immune complex-mediated inflammation may be involved. Necrotizing arteritis in env-pX rats mimicking polyarteritis nodosa in humans also seems to be irrelevant to the pathogenetic immune complexes, because only IgM but not IgG or complements is deposited in affected vessels and distributed IgG suggesting a nonspecific permeation is evident around the lesion (data not shown).

Because necrotizing arteritis similar to that seen in env-pX rats occurred in nontransgenic rats given adoptive transfers of env-pX SCs, the env-pX transgene in affected vessels may not be essential for the development of arteritis. In addition, based on findings that the infiltrating cells contained T cells and that adoptive transfers of env-pX SCs but not BMCs induced necrotizing arteritis in nontransgenic rats, we assumed that T cells derived from the env-pX thymus may play an important role in the development of necrotizing arteritis in env-pX rats. Results of reciprocal exchange of the thymus frameworks between env-pX and nontransgenic rats (Tx+TT+BMT experiment) clearly showed that our hypothesis is tenable. Sumita and colleagues25 established a T cell clone that recognized rat vascular smooth muscle cells from MRL-+/+ mice, and they demonstrated that an adoptive transfer of these T cells induced pulmonary vasculitis in MRL-+/+ mice. The env-pX SCs may possibly contain autoreactive T cells that recognize vascular components unrelated to the env-pX transgene, although SC donors at the time of transfer experiments did not manifest arteritis. Further investigations are needed to clarify which population of SCs is directly associated with the development of necrotizing arteritis in env-pX rats, and to identify the target molecule(s) of vascular components recognized by these cells.

Because the env-pX transgene was not detected in the arteritis lesion of a Tx+TT+BMT recipient, it seems unlikely that contaminated cells derived from the env-pX thymic tissue accumulated or expanded at the lesion. It is considered that nontransgenic T cells reactive with self-vascular components may be generated or may not be deleted with an interaction with the env-pX thymus framework. Autoreactive T cells are eliminated through positive and negative selections in the thymus.26 Out of regulation of either positive or negative selection in the thymus results in escape of autoreactive T cells from apoptosis.26,27 Because p40Tax encoded by the HTLV-I env-pX region regulates the expression of several genes of host cells,28,29 functional alteration may be induced in the thymus framework carrying the env-pX transgene. What type of alteration occurs in the env-pX thymus, and which is critical for development of necrotizing arteritis has to be determined. T cell differentiation assays in reaggregation cultures of thymus frameworks and thymocytes,30 and comprehensive gene analysis of the thymus using cDNA microarray (these investigations are ongoing) would provide helpful information in this regard.

In summary, this report is the first evidence that the thymus is directly associated with development of necrotizing arteritis. Our model provides a novel approach in the search for the pathogenesis of vasculitis syndromes, including polyarteritis nodosa, in humans.


   Acknowledgements
 
We thank Dr. Y. Matsumoto (Tokyo Metropolitan Institute for Neuroscience) for instructions on thymectomy; C. Sudo, M. Tateyama, and K. Nakase for technical assistance; M. Ishizaka for secretarial services.


   Footnotes
 
Address reprint requests to Takashi Yoshiki, M.D., Ph.D., Department of Pathology/Pathophysiology, Division of Pathophysiological Science, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Kita-ku, Sapporo 060-8638, Japan. E-mail: path1{at}med.hokudai.ac.jp

Supported by grants from the Ministries of Education, Science, Technology, Sports, and Culture, and Health, Labour, and Welfare, of Japan, the Takeda Science Foundation, and the Japan Rheumatism Foundation.

Accepted for publication May 24, 2002.


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 Materials and Methods
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