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Japanese Journal of Clinical Oncology Pages 97-103

CD4- and TCR[alpha][beta]-positive T Lymphocytes Predominantly Infiltrated into Well-Moderately Differentiated Colon Adenocarcinoma Tissues
Introduction
Subjects And Methods
   Patients
   Preparation of Tissues
   Monoclonal Antibodies
   Enzyme Immunostaining
   Statistical Analysis
Results
Discussion
Acknowledgments
References
CD4- and TCR[alpha][beta]-positive T Lymphocytes Predominantly Infiltrated into Well-Moderately Differentiated Colon Adenocarcinoma Tissues

CD4- and TCR[alpha][beta]-positive T Lymphocytes Predominantly Infiltrated into Well-Moderately Differentiated Colon Adenocarcinoma Tissues

Shunji Matsuda1, Tetsumi Yamane2, Masayasu Hamaji3

1Institute of Clinical Research, 2Department of Pathology and 3Department of Surgery, Kure National Hospital, Kure, Hiroshima, Japan

Intraepithelial T lymphocytes have been reported as being functional in the growth of epithelial cells and also in the discrimination of aberrant cells, whereas their function against colon adenocarcinoma cells is obscure. The phenotype of colon intraepithelialT lymphocytes has been found in patients with inflammatory bowel diseases but not in patients with colon adenocarcinoma. In this study, we investigated cell surface markers of tumor-infiltrating T lymphocytes of adenocarcinoma of the colon and rectum at various grades of differentiation and intraepithelial T lymphocytes of adjacent normal colon by enzyme immunostaining. Among intraepithelial T lymphocytes of the normal colon, CD8- and TCR[gamma][delta]-positive T lymphocytes were predominant as described. In contrast, tumor-infiltrating T lymphocytes of well-moderately differentiated adenocarcinoma of the colon and rectum were predominantly CD4- and TCR[alpha][beta]-positive. The decrease of TCR[gamma][delta]-positive T lymphocytes and the increase of CD4 and TCR[alpha][beta]-positive T lymphocytes in adenocarcinoma tissues of the colon and rectum suggests that an alteration of the local immune system participates in the formation of adenoma and/or adenocarcinoma of the colon and rectum, resulting in infiltration of CD4-positive T lymphocytes that have certain activity against transformed cells.

Key words: T lymphocyte - TCR - adenocarcinoma - colon

INTRODUCTION

Murine intestinal intraepithelial T lymphocytes (IELs), which are localized in the space between intestinal epithelial cells, have been extensively studied (1). IELs have been divided into two groups according to the expression of surface molecules. One group consists of T lymphocytes that express TCR[alpha][beta] and either CD4 or CD8[alpha][beta] on the surface. They are thought to be differentiated in the thymus like T lymphocytes in peripheral blood and spleen. The other group consists of T lymphocytes that express CD8[alpha][alpha] and either TCR[alpha][beta] or TCR[gamma][delta] on the surface and they are thought to be differentiated at mucosal sites. Among these IELs, TCR[gamma][delta]-positive T lymphocytes may play unique roles. They are localized only in the intestinal intraepithelial space and have cytotoxic activity (2). Additionally, immunoregulatory functions of these cells have been identified. IELs that express TCR[gamma][delta] also secrete cytokines (3,4), act with TCR[alpha][beta] T lymphocytes (5) and play an important role in microbial infection (6,7). TCR[gamma][delta] IELs produce keratinocyte growth factor (KGF) and activate the growth of rat intestinal epithelial cells (8,9). These results indicate the unique role of TCR[gamma][delta]-positive IELs in maintaining intestinal epithelial cells, including the exclusion of aberrant cells. However, few studies have been published about these cells in humans. In the colon, 40% of human IELs express TCR[gamma][delta] and the number of TCR[gamma][delta] IELs decreases significantly in inflammatory bowel diseases [horbar] Crohn's disease and ulcerative colitis (10,11). Evidence that CD8-positive IELs isolated from the normal human jejunum are cytotoxic against human colon carcinoma cell lines (12,13) suggests a unique role of human IELs against the onset of colon adenoma and adenocarcinoma. These two types of tumor originate from colon epithelial cells and they may be partially under the control of the mucosal immune system, including IELs. However, changes in IEL populations during the onset of colon adenoma and/or adenocarcinoma have not been defined. Therefore, we investigated the phenotype of tumor-infiltrating T lymphocytes expressing TCRs and CD4/8 in human colon and rectum adenocarcinoma tissues and compared them with those in an adjacent normal colon.

SUBJECTS AND METHODS

Patients

Twenty patients who were diagnosed with colon or rectum carcinoma were admitted for surgical resection of the carcinoma. The patients' profiles are shown in Table 1. The average age was 62.2 years (range 28-86 years). Eight patients were male and 12 were female. The sites of carcinoma were ascending colon (five patients), descending colon (four patients), sigmoid colon (four patients), cecum (four patients) and rectum (three patients).

Preparation of Tissues

Small pieces of carcinoma tissue and adjacent normal colon, at least 10 cm away from the carcinoma, were obtained immediately after surgical resection. After washing in PBS, tissues were divided into two pieces for hematoxylin and eosin (HE) staining and enzyme immunostaining. For HE staining, tissues were fixed in formalin and processed by standard methods. For enzyme immunostaining, the tissues were fixed with periodate-lysine-2% paraformaldehyde (PLP) (14). Briefly, tissues were fixed in PLP for 6 h at 4°C and permeated with 0.1 M phosphate buffer (pH 7.4) containing 7.5, 15 and 20% sucrose by rotating for 12 h at 4°C. Subsequently, the tissues were embedded in Tissue-Tek OCT compound (Miles, Elkhart, IN, USA) and snap-frozen in acetone-dry ice. Sections 6-8 mm thick were prepared on silanized slide glasses (DAKO Japan, Kyoto, Japan) using a cryostat (Bright Instruments, Cambridge, UK) at -30°C, air dried and stored at -80°C in closed plastic boxes until use.

Monoclonal Antibodies

To stain surface molecules on T lymphocytes, we used mouse monoclonal antibodies against CD3, CD4, CD8 (Becton Dickinson, San Jose, CA, USA), TCR[alpha][beta] and TCR[gamma][delta] (Identi-T bF1 and d1, T cell Diagnostics, Cambridge, MA, USA). Monocyte/macrophages and NK cells were stained with monoclonal antibodies against CD14 and CD56 (Nippon Becton Dickinson, Tokyo, Japan), respectively. All monoclonal antibodies were diluted to 1:50 with PBS and each section was stained in 50 µl of diluent.

Enzyme Immunostaining

Thin sections were washed in PBS, then endogenous peroxidase activity was blocked by incubation with 3% superoxide for 30 min at room temperature (RT). The sections were incubated with diluted normal rabbit or goat serum, followed by diluted monoclonal antibodies for 1 h at RT or for 16 h at 4°C. After washing in PBS, bound monoclonal antibodies were visualized by the biotin-streptavidin system using a commercial kit (DAKO LSAB kit, DAKO Japan). Sections were counterstained with methyl green or hematoxylin. In some experiments, tissue sections were double-stained with two monoclonal antibodies using a commercial kit (Histostan-DS kit, Zymed Laboratories, South San Francisco, CA, USA). Briefly, after staining with a monoclonal antibody, tissue sections were stained again with the monoclonal antibody against CD3. The number of stained cells was counted under a light microscope and the percentage of surface molecule-positive cells against CD3-positive T cells was calculated.

Table 1. Patients with colon adenocarcinoma
Patient Age (years)/gender Site of carcinoma Histopathological diagnosis
1 58/F Cecum Well differentiated adenocarcinoma in villous adenoma
2 57/F Colon (desc.) Well differentiated adenocarcinoma
3 28/F Colon (sigmoid) Moderately differentiated adenocarcinoma
4 86/M Colon (asc.) Well differentiated adenocarcinoma
5 67/M Colon (sigmoid) Moderately differentiated adenocarcinoma
6 47/F Cecum Well differentiated adenocarcinoma in villous adenoma
7 70/M Cecum Poorly differentiated adenocarcinoma
8 61/F Cecum Moderately differentiated adenocarcinoma
9 72/M Colon (asc.) Well differentiated adenocarcinoma
10 67/F Colon (asc.) Moderately differentiated adenocarcinoma
11 54/M Colon (desc.) Well differentiated adenocarcinoma
12 51/M Colon (asc.) Moderately differentiated adenocarcinoma
13 69/M Colon (asc.) Moderately differentiated adenocarcinoma
14 60/F Colon (sigmoid) Poorly - moderately differentiated adenocarcinoma
15 66/M Colon(sigmoid) Well differentiated adenocarcinoma
16 63/F Rectum Well differentiated adenocarcinoma in villous adenoma
17 36/M Rectum Well differentiated adenocarcinoma
18 80/F Rectum Well differentiated adenocarcinoma
19 72/F Colon (desc.) Moderately differentiated adenocarcinoma
20 79/F Colon (desc.) Moderately differentiated adenocarcinoma
M, male; F, female; desc., descending; asc., ascending.

Statistical Analysis

The statistical significance between the percentages of positive cells was determined using the Mann-Whitney U test.

RESULTS

Histopathological diagnoses were performed on each tissue section stained with HE. Grades of differentiation of each carcinoma were poorly-moderately differentiated in two, moderately differentiated in eight and well differentiated in ten patients. Three sections from patients with well differentiated adenocarcinoma also revealed villous adenoma (Table 1).

To examine the specificity of monoclonal antibodies, lymphoid follicles in the lamina propria of normal colon were stained with antibodies. Most cells in the T cell area of lymphoid follicles were stained by monoclonal antibody against CD3 and many cells by those against CD4 and TCR[alpha][beta]. In contrast, the monoclonal antibody against CD8 stained few cells in the T cell area and that against TCR[gamma][delta] hardly stained T cells in lymphoid follicles (Fig. 1). These results defined the well preserved antigenicity of the molecules on the cell surface after PLP fixation and the fine specificity of the monoclonal antibodies that we used.


Figure 1. Staining of lymphoid follicles in normal colon with mouse monoclonal antibodies against the molecules on the surface of T lymphocytes. Lymphoid follicles were stained with monoclonal antibodies against CD4 (A), CD8 (B), TCR[alpha][beta] (C) and TCR[gamma][delta] (D). Antibody-positive lymphocytes show a brown color.

Tissue sections from a patient with well differentiated adenocarcinoma in villous adenoma (patient 1) were stained with the monoclonal antibodies. Similar numbers of CD4- and CD8-positive T lymphocytes were found in both the lamina propria and intraepithelial space in the normal part of the colon. TCR[alpha][beta]- and TCR[gamma][delta]-positive lymphocytes were predominant in the lamina propria and intraepithelial space, respectively. Intraepithelial T lymphocytes were mostly present near the basal side of epithelial cells. In the adenocarcinoma tissue, CD4- and TCR[alpha][beta]-positive T lymphocytes were predominant in both the lamina propria and the intraepithelial space (Fig. 2). The ratio of CD4-, CD8-, TCR[alpha][beta]- and TCR[gamma][delta]-positive T lymphocytes to CD3-positive lymphocytes (mature T lymphocytes) was calculated on tissue sections double-stained with monoclonal antibodies (Table 2). In the adjacent normal colon, 68 and 77% of intraepithelial T lymphocytes were positive for CD8 and TCR[gamma][delta], respectively. In contrast, in adenocarcinoma tissue, intraepithelial T lymphocytes were 76% positive for CD4 and 90% positive for TCR[alpha][beta]. Other sections were stained and evaluated in the same manner. Poorly-moderately differentiated adenocarcinoma showed the opposite results. The frequency of both CD4- and TCR[alpha][beta]-positive lymphocytes was lower than that of CD8- and TCR[gamma][delta]-positive lymphocytes in the intraepithelial space of these tissues. The average ratio of surface molecule-positive lymphocytes was calculated from the results for all 20 patients (Table 3).


Figure 2. Localization of CD4- (A), CD8- (B), TCR[alpha][beta]- (C) and TCR[gamma][delta]-positive (D) lymphocytes in adenocarcinoma tissue from a patient with colon well differentiated adenocarcinoma in villous adenoma. Antibody-positive lymphocytes show a brown color and CD3-positive lymphocytes a blue color.

Table 2. Ratio of T lymphocytes in colon adenocarcinoma and colon of a patient with adenocarcinoma in villous adenoma (patient 1) (%)
Cell surface molecule Adenocarcinoma Colon
  Tumor-infiltrating
lymphocytes		 Lamina propria
lymphocytes		 Intraepithelial
lymphocytes		 Lamina propria
lymphocytes
CD4 76 85 21 54
CD8 4 11 68 38
TCR[alpha][beta] 90 81 10 37
TCR[gamma][delta] 0 20 77 3
The percentage of positive cells was calculated by comparison with CD3-positive cells. Means ± SD.

Table 3. Means of the ratio of T lymphocytes in carcinoma tissue and normal colon of 20 patients with adenocarcinoma of the colon and rectum (%)
Cell surface molecule Adenocarcinoma Colon
  Tumor-infiltrating
lymphocytes		 Lamina propria
lymphocytes		 Intraepithelial
lymphocytes		 Lamina propria
lymphocytes
CD4 49.2 ± 30.4 62.3 ± 15.6 23.7 ± 12.6 57.4 ± 17.1
CD8 33.2 ± 22.1 26.2 ± 13.0 68.6 ± 20.7 35.0 ± 11.0
TCR[alpha][beta] 44.7 ± 25.4 44.0 ± 15.0 37.6 ± 19.7 44.7 ± 9.0
TCR[gamma][delta] 23.0 ± 23.6 11.9 ± 5.1 62.3 ± 17.8 14.3 ± 11.0
The percentage of positive cells was calculated by comparison with CD3-positive cells. Means ± SD.

In the lamina propria of both adenocarcinoma tissue and normal colon, the frequency of CD4-, TCR[alpha][beta]- and TCR[gamma][delta]-positive T lymphocytes was not significantly different (CD4, p > 0.3; CD8, p = 0.05; TCR[alpha][beta], p > 0.6; TCR[gamma][delta], p > 0.6). However, the frequency of CD4-positive T lymphocytes was significantly higher and the frequency of CD8- and TCR[gamma][delta]-positive T lymphocytes was significantly lower in tumor-infiltrating lymphocytes of adenocarcinoma than those in intra-epithelial lymphocytes of the adjacent normal colon. (CD4, p = 0.004; CD8, p < 0.001; TCR[alpha][beta], p > 0.3; TCR[gamma][delta], p < 0.001). The ratios of CD4- to CD8-positive T lymphocytes and of TCR[alpha][beta]- to TCR[gamma][delta]-positive T lymphocytes were calculated for each tissue section (Fig. 3). In the lamina propria, both ratios were the same between adenocarcinoma and the normal colon. In the intraepithelial space of normal colon, both ratios were <1.0, except for a few tissues, indicating that CD8- and TCR[gamma][delta]-positive T lymphocytes are predominant in the intraepithelial space in the normal colon. However, in tumor-infiltrating lymphocytes, both ratios were increased and were similar to those in the lamina propria. Furthermore, CD4-positive tumor-infiltrating T lymphocytes tended to increase only in patients with well and moderately differentiated adenocarcinomas (Fig. 4), whereas the ratio was not related to the grade of infiltration of the adenocarcinoma (Duke's classification). Tissues from the patients with poorly differentiated adenocarcinoma were fibrous and lymphocytes were relatively sparse. There were few CD14- and CD56-positive cells (<1% of CD3-positive lymphocytes) in the tissue sections from all patients.

DISCUSSION

We found that CD8-positive T cells and TCR[gamma][delta]-positive T lymphocytes, which were predominant in the intraepithelial space of the normal colon, were significantly decreased in the space of adenoma and adenocarcinoma cells, especially in well-moderately differentiated adenocarcinomas. CD4- and TCR[alpha][beta]-positive T lymphocytes were predominant in the intraepithelial space. Similar findings from chronic inflammatory bowel diseases such as Crohn's disease and ulcerative colitis have been reported (10,11). In the study, TCR[gamma][delta]-positive IELs constituted 40% of cells in the normal colon and decreased to 12 and 5% in Crohn's disease and ulcerative colitis, respectively, whereas there were few of these cells in the lamina propria (3-6%) in both the normal colon and inflammatory bowel diseases. In our study, TCR[gamma][delta] IELs accounted for 62.3 ± 17.8% of the CD3-positive lymphocytes in the normal colon and decreased to 23.0 ± 23.6% in the space between adenoma and adenocarcinoma cells, as they do in inflammatory bowel diseases. The frequency of the cells in the lamina propria of the normal colon and adenoma/adenocarcinoma was similar at 14.3 ± 11.0 and 11.9 ± 5.1%, respectively. The small difference in the frequency of TCR[gamma][delta]-positive T lymphocytes between the present study and previous reports may be due to staining procedures and monoclonal antibodies. The ratio of TCR-positive T lymphocytes in the lamina propria was low (40-60%). This may be due to the different appearance of antibody-binding epitopes between CD3 and TCR during intestinal T cell maturation or the binding of monoclonal antibodies which we used in this study ([beta]F1 and TCR[delta]1) to special subsets of TCR.


Figure 3. Comparison of the ratio of CD4- to CD8-positive T lymphocytes (A) and the ratio of TCR[alpha][beta]- to TCR[gamma][delta]-positive T lymphocytes (B) in tumor-infiltrating lymphocytes (TIL), lamina propria lymphocytes (LPL) and intraepithelial lymphocytes of normal colon (IEL). Mean values are shown by horizontal bars.


Figure 4. Relationship between the ratio of CD4- to CD8-positive lymphocytes and the grade of differentiation of adenocarcinoma (A) and Duke's classification (B). Mean values are shown by horizontal bars.

The increase in TCR[alpha][beta]-positive T cells was significant only in the space of well differentiated adenocarcinoma cells. Additionally, the ratio of CD4-positive T lymphocytes to CD8-positive T lymphocytes differed even among well-moderately differentiated adenocarcinoma tissues. The reason why CD4 and TCR[alpha][beta]-positive T lymphocytes are increased at different levels even in the same well differentiated adenocarcinoma is obscure. The expression of unknown tumor-specific antigens on well differentiated adenocarcinoma cells may be related to the infiltration of CD4- and TCR[alpha][beta]-positive T lymphocytes.

Ebert and co-workers (12,13) have reported that IELs isolated from the normal jejunum were cytotoxic against human colon carcinoma cell lines and that the cytotoxic lymphocytes were mainly CD8-positive, suggesting that CD8-positive T lymphocytes play a role in discriminating transformed cells. In contrast, CD4-positive T lymphocytes, which were predominant in the intracellular space of adenoma/adenocarcinoma tissues in our study, are also present in colon carcinoma tissues (15) and have cytotoxic activity through class II MHC (16). Taken together, it was suggested that TCR[gamma][delta]-positive IELs, which play an important role in the maintenance of normal colon epithelial cells (8,9), are decreased in colon adenocarcinoma and that CD4- and TCR[alpha][beta]-positive T lymphocytes, which may have cytotoxic activity against transformed cells, increase to eliminate the carcinoma cells. Recently, Taniguchi and co-workers (17,18) reported that NK T cells (TCR V[alpha]24-positive T lymphocytes) may have functions for the inhibition of metastasis of tumor cells and tumor cell killing. Further investigations are required to elucidate the origin and the functions of the tumor-infiltrating CD4- and TCR[alpha][beta]-positive lymphocytes.

Acknowledgments

This work was supported by a grant for cancer research from the Japanese Ministry of Health and Welfare. We thank Drs K. Nozaki (President of Kure National Hospital) and M. Miyata (Director of the Institute of Clinical Research, Kure National Hospital) for their kind support of this study. Some parts of the results have been published in a booklet (19).

References

1. Klein JR, Mosley RL. Phenotypic and cytotoxic characteristics of intraepithelial lymphocytes. In: Kiyono H, McGee JR, editors. Advances in Host Defense Mechanisms, Vol. 9, Mucosal Immunology: Intraepithelial Lymphocytes. New York: Raven Press, 1993;21-31.

2. Lefrancois L, Goodman T. In vivo modulation of cytolytic activity and Thy-1 expression in TCR-[gamma][delta] intraepitherial lymphocytes. Science 1989;243: 1716-8. MEDLINE Abstract

3. Taguchi T, Aicher WK, Fujihashi K, Yamamoto M, McGhee JR, Bluestone JA, et al. Novel function for intestinal intraepithelial lymphocytes. Murine CD3+, [gamma]/[delta] T cells produce IFN-[gamma] and IL-5. J Immunol 1992;147:3736-44.

4. Barrett TA, Gajewski TF, Danielpour D, Chang EB, Beagley KW, Bluestone JA. Differential function of intestinal intraepithelial lymphocyte subsets. J Immunol 1992;149:1124-1130. MEDLINE Abstract

5. Kaufman SHE, Blum C, Yamamoto S. Crosstalk between [alpha]/[beta] T cells and [gamma]/[delta] T cells in vivo: Activation of [alpha]/[beta] T-cell responses after [gamma]/[delta] T-cell modulation with the monoclonal antibody GL3. Proc Natl Acad Sci USA 1993;90:9620-4.

6. Momgaerts P, Arnoldi J, Russ F, Tonegawa S, Kaufmann SHK. Different roles of [alpha][beta] and [gamma][delta] T cells in immunity against an intracellular bacterial pathogen. Nature 1993;362:53-6.

7. Lusso P, Garzino-Demo A, Crowley RW, Malnati MS. Infection of [gamma]/[delta] T lymphocytes by human herpes virus 6: Transcriptional induction of CD4 and susceptibility to HIV infection. J Exp Med 1995;181:1303-10. MEDLINE Abstract

8. Boismenu R, Havran WL. Modulation of epithelial cell growth by intraepithelial [gamma][delta] T cells. Science 1994;266:1253-5. MEDLINE Abstract

9. Housley RM, Morris CF, Boyle W, Ring R, Biltz R, Tarpley JT, et al. Keratinocyte growth factor induces proliferation of hepatocytes and epithelial cells throughout the rat gastrointestinal tract. J Clin Invest 1994;94:1764-77. MEDLINE Abstract

10. Fukushima K, Masuda T, Ohtani H, Sasaki I, Funayama Y, Matsuno S, et al. Immunohistochemical characterization, distribution and ultrastructure of lymphocytes bearing the gamma/delta T-cell receptor in the human gut. Virchows Arch B 1991;60:7-13.

11. Fukushima K, Masuda T, Ohtani H, Sasaki I, Funayama Y, Matsuno S, et al. Immunohistochemical characterization, distribution and ultrastructure of lymphocytes bearing the gamma/delta T-cell receptor in inflammatory bowel disease. Gastroentrology 1991;101:670-8.

12. Taunk J, Roberts AI, Ebert EC. Spontaneous cytotoxicity of human intraepitherial lymphocytes against epithelial cell tumors. Gastroenterology 1992;102:69-75. MEDLINE Abstract

13. Roberts AI, O'Connell SM, Ebert EC. Intestinal intraepitherial lymphocytes bind to colon cancer cells by HML-1 and CD11a. Cancer Res 1993;53:1608-11. MEDLINE Abstract

14. MacLean IW, Nakane PK. Periodate-lysine-paraformaldehyde fixative. A new fixative for immunoelectron microscopy. J Histochem Cytochem 1974;22:1077-84.

15. Hom SS, Rosenberg SA, Topalian SL. Specific immune recognition of autologous tumor by lymphocytes infiltrating colon carcinomas: analysis by cytokine secretion. Cancer Immunol Immunother 1993;36:1-8. MEDLINE Abstract

16. Muller D, Killer BH, Whitton JL, Lepan KE, Brigman KK, Frelinger JA. LCMV-specific class II-restricted cytotoxic T-cells in [beta]2 microglobulin deficient mice. Science 1992;255:1576-8. MEDLINE Abstract

17. Sumida T, Sakamoto A, Murata H, Makino Y, Takahashi H, Yoshida S, et al. Selective reduction of T cells bearing invariant V alpha 24J alpha Q antigen receptor in patients with systemic sclerosis. J Exp Med 1995;182:1163-8. MEDLINE Abstract

18. Masuda K, Makino Y, Cui J, Ito T, Tokuhisa T, Takahama Y, et al. Phenotypes and invariant alpha beta TCR expression of peripheral V alpha 14+ NK T cells. J Immunol 1997;158:2076-82.18. Matsuda S. Increase of CD4 and TCRd[beta]-positive cells in colon cancer. Editor: Kondo M, My Life Co., Tokyo, Japan. Booklet: Digestive Organ and Mucosal Immunology 1966:33.

Received June 2, 1997; accepted September 8, 1997
For reprints and all correspondence: Shunji Matsuda, Institute of Clinical Research, Kure National Hospital, 3-1, Aoyama-cho, Kure, Hiroshima 737, Japan
Abbreviations: TCR, T cell receptor; IEL, intraepithelial T lymphocyte; KGF, keratinocyte growth factor; HE, hematoxylin and eosin; PLP, periodate-lysine-2% paraformaldehyde

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