Effects of an immunosuppressive treatment on the rat prostate

Figures & data

Table 1 Study scheme

Group	Number of rats	Given drugs (pharmaceutical form)	Dose (mg/kg of body weight/day)	Feeding time
I	6	–	–	–
II	6	Rapa (Rapamune; Pfizer, Inc., New York, NY, USA)	0.5	6 months
		Tac (Prograf; Astellas Pharma Inc., Tokyo, Japan)	4
		Pred (Encorton; Polfa, Pabianice, Poland)	4
III	6/4	Rapa (Rapamune)	0.5	6 months
		CsA (Sandimmum-Neoral; Novartis International AG, Basel, Switzerland)	5
		Pred (Encorton)	4
IV	6	Rapa (Rapamune)	0.5	6 months
		MMF (CellCept; Hoffman-La Roche Ltd., Basel, Switzerland)	20
		Pred (Encorton)	4
V	6	CsA (Sandimmum-Neoral)	5	6 months
		MMF (CellCept)	20
		Pred (Encorton)	4
VI	6	CsA (Sandimmum-Neoral)	5	First 3 months
		MMF (CellCept)	20
		Pred (Encorton)	4
		Rapa (Rapamune)	0.5	Last 3 months
VII	6	Tac (Prograf)	4	6 months
		MMF (CellCept)	20
		Pred (Encorton)	4
VIII	6	Tac (Prograf)	4	First 3 months
		MMF (CellCept)	20
		Pred (Encorton)	4
		Rapa (Rapamune)	0.5	Last 3 months

Notes: Drugs were given to rats in accordance with the regimens applied in clinical practice. I, control group; II–VIII, experimental groups. 6/4: Two rats died in the fourth month of the experiment.

Abbreviations: CsA, cyclosporin A; MMF, mycophenolate mofetil; Pred, prednisone; Rapa, rapamycin; Tac, tacrolimus.

Table 2 Body mass of rats

Group	Given drugs	Body mass (g)
		$\overline{x}$ ± SD	Me	Min–max
I	–	572.9±78.1	574	474–700
II	Rapa, Tac, Pred	403.0*±54.3	417	331–480
III	Rapa, CsA, Pred	467.0±54.9	470	398–530
IV	Rapa, MMF, Pred	435.7±58.3	414	385–546
V	CsA, MMF, Pred	544.2±50.2	554	481–600
VI	CsA, MMF, Pred/Rapa	428.8±53.9	472.5	411–563
VII	Tac, MMF, Pred	482.5±66.7	482.5	405–580
VIII	Tac, MMF, Pred/Rapa	502.8±38.5	494.5	465–569

Notes: I, control group; II–VIII, experimental groups.

* P<0.05.

Abbreviations: CsA, cyclosporin A; Me, median; Min-max, minimum-maximum values; MMF, mycophenolate mofetil; Rapa, rapamycin; Pred, prednisone; Tac, tacrolimus; $\overline{x}$ ± SD, mean ± standard deviation.

Figure 1 Morphology of the rat dorsolateral prostate.

Notes: (A) Epithelial cells (arrows) of the control group (I). (B) Numerous papillary infoldings of the glandular epithelium protruding into the acini lumen (arrows), hyperplastic epithelium, group III. (C) Inflammatory cells in the lumen of some acini (arrows), group IV. (D) Distinctly atrophic epithelium (arrows), group V. (E) Disorder of the normal structure of the epithelium (arrows), cells of different height, focal hyperplasia, group VI. (F) Edema (arrows) in the walls of acini in the stroma, group VIII. H&E staining, magnification ×600. I: control group; III, IV, V, VI and VIII: experimental groups.
Abbreviation: H&E, hematoxylin and eosin.

Figure 2 Ultrastructure of the rat dorsolateral prostate.

Notes: (A) Proper cisterns of the rough endoplasmic reticulum in the perinuclear region (arrow) of the control group (I), ×10,200. (B) Bloated cisterns of the rough endoplasmic reticulum (arrows). Group III, ×10,200. (C) Epithelium showing the features of atrophy with movement of the secretion apparatus from the supernuclear region to the side part of the cell (arrow), group V, ×6,600. (D) Bloated cisterns of the Golgi apparatus (arrow), group VIII, ×6,600. I: control group; III, V and VIII: experimental groups.

Figure 3 Immunolocalization and immunoexpression of PCNA (A, B), cytokeratin (C, D), and desmin (E, F) in the rat dorsolateral prostate.

Notes: (A, B) PCNA-positive cells of the glandular epithelium (arrows). (A) Control group (I), (B) group III. (C, D) Cytokeratin-positive cells of the glandular epithelium (arrows). (C) Control group (I), (D) group VII. (E, F) Desmin-positive cells of the smooth myocytes around acini (arrows). (E) Control group (I), (F) group VII. Magnification ×600. I: control group; III and VII: experimental groups.
Abbreviation: PCNA, proliferating cell nuclear antigen.

Figure 4 Percentage of PCNA-positive cells in epithelium and stroma in the rat dorsolateral prostate in control (I) and experimental groups (II–VIII).

Notes: a, significantly different vs the controls in epithelial cells; b, groups with the conversion of the treatment to Rapa, significantly different vs the groups without Rapa in epithelial cells (VI vs V and VIII vs VII); c, significantly different vs controls in stromal cells; d, groups with the conversion of the treatment to Rapa, significantly different vs the groups without Rapa in stromal cells (VI vs V and VIII vs VII); e, PCNA-positive epithelial cells, significantly different vs PCNA-positive stromal cells.
Abbreviations: CsA, cyclosporin A; MMF, mycophenolate mofetil; Rapa, rapamycin; PCNA, proliferating cell nuclear antigen; Pred, prednisone; Tac, tacrolimus.

Figure 5 Percentage of cytokeratin-positive cells in epithelium in the rat dorsolateral prostate in control (I) and experimental groups (II–VIII).

Notes: a, significantly different vs the controls for the cells with weak expression; b, significantly different vs the controls for the cells with moderate expression; c, significantly different vs the controls for the cells with strong expression; d, groups with the conversion of the treatment to Rapa, significantly different vs the groups without Rapa (VI vs V and VIII vs VII) for the cells with weak expression; e, groups with the conversion of the treatment to Rapa, significantly different vs the groups without Rapa (VI vs V and VIII vs VII) for the cells with strong expression.
Abbreviations: CsA, cyclosporin A; MMF, mycophenolate mofetil; Rapa, rapamycin; Pred, prednisone; Tac, tacrolimus.

Figure 6 Percentage of desmin-positive cells in epithelium in the rat dorsolateral prostate in control (I) and experimental groups (II–VIII).

Notes: a, significantly different vs the controls for the cells with weak expression; b, significantly different vs the controls for the cells with moderate expression; c, significantly different vs the controls for the cells with strong expression; d, groups with the conversion of the treatment to Rapa, significantly different vs the groups without Rapa (VI vs V and VIII vs VII) for the cells with weak expression; e, groups with the conversion of the treatment to Rapa, significantly different vs the groups without Rapa (VI vs V and VIII vs VII) for the cells with moderate expression; f, groups with the conversion of the treatment to Rapa, significantly different vs the groups without Rapa (VI vs V and VIII vs VII) for the cells with strong expression.
Abbreviations: CsA, cyclosporin A; MMF, mycophenolate mofetil; Rapa, rapamycin; Pred, prednisone; Tac, tacrolimus.

Table S1 Percentage of PCNA-positive epithelial and stromal cells in the rat dorsolateral prostate in control (I) and experimental (II–VIII) groups

Group	Given drugs	PCNA-positive cells in epithelium (%)			PCNA-positive cells in stroma (%)
		Min–max	Me	$\overline{x}$± SD	Min–max	Me	$\overline{x}$± SD
I	–	12.7–30.4	22.3	22.3±4.1	6.5–25.0	15.6	16.0±3.6
II	Rapa, Tac, Pred	15.2–31.6	22.4	22.5±4.0	10.0–25.4	16.9	16.6±3.8
III	Rapa, CsA, Pred	17.7–36.7	30.0	29.3*±4.6	12.5–28.4	18.0	18.6*±3.9
IV	Rapa, MMF, Pred	23.5–36.0	30.8	30.0*±3.3	11.8–24.3	18.3	18.3±3.6
V	CsA, MMF, Pred	17.2–31.0	22.5	22.9±3.3	9.6–25.0	15.8	17.2±4.5
VI	CsA, MMF, Pred/Rapa	10.1–31.3	15.7	16.0a,*±4.2	9.0–25.0	14.8	14.8a±3.6
VII	Tac, MMF, Pred	16.1–34.8	23.7	24.3±4.8	10.9–23.6	16.6	16.4±2.9
VIII	Tac, MMF, Pred/Rapa	8.6–23.3	15.8	16.6a,*±3.2	3.8–17.4	12.1	11.1a,*±3.7

Notes:

* P<0.05 vs control.

a Groups with the conversion of the treatment to Rapa, significantly different (P<0.05) vs the groups without Rapa (VI vs V and VIII vs VII).

Abbreviations: CsA, cyclosporin A; Me, median; Min-max, minimum-maximum values; MMF, mycophenolate mofetil; Rapa, rapamycin; PCNA, proliferating cell nuclear antigen; Pred, prednisone; Tac, tacrolimus; $\overline{x}$ ± SD, mean ± standard deviation.

Table S2 Percentage of cytokeratin-positive cells in the rat dorsolateral prostate in control (I) and experimental (II–VIII) groups

Group	Given drugs	Cells with weak expression of cytokeratin (%)			Cells with moderate expression of cytokeratin (%)			Cells with strong expression of cytokeratin (%)
		Min–max	Me	$\overline{x}$± SD	Min–max	Me	$\overline{x}$± SD	Min–max	Me	$\overline{x}$± SD
I	–	36.1–71.0	58.8	58.4±7.3	1.0–30.7	13.2	14.4±8.5	0.1–7.7	0.6	1.6± 1.8
II	Rapa, Tac, Pred	16.0–50.7	41.8	39.5*±8.3	16.6–53.9	37.9	36.2*±9.7	6.5–38.0	14.4	16.0*±7.0
III	Rapa, CsA, Pred	19.4–49.7	30.7	32.2*±7.5	26.3–57.2	43.9	43.0*±6.9	4.3–42.3	22.3	21.0*±9.8
IV	Rapa, MMF, Pred	10.0–39.2	23.9	24.7*±7.3	20.7–56.5	46.6	44.2*±8.0	9.3–44.8	25.3	26.1*±9.6
V	CsA, MMF, Pred	10.4–45.6	28.9	28.2*±7.6	34.9–55.0	45.2	44.2*±5.5	9.6–47.1	23.2	24.5*±8.8
VI	CsA, MMF, Pred/Rapa	18.3–54.4	31.2	30.5*±8.3	10.1–51.2	40.8	38.8*±9.0	1.5–39.7	22.9	22.9*±9.6
VII	Tac, MMF, Pred	4.1–34.3	16.3	17.6*±6.7	21.8–50.1	38.1	37.3*±7.4	21.2–61.8	43.7	44.0*±9.6
VIII	Tac, MMF, Pred/Rapa	11.2–45.3	28.7	27.8a,*±8.9	18.4–50.7	33.0	34.8*±7.7	14.6–46.6	30.4	30.4a,*±9.8

Notes:

* P<0.05 vs control.

a Groups with the conversion of the treatment to Rapa, significantly different (P<0.05) vs the groups without Rapa (VI vs V and VIII vs VII).

Abbreviations: CsA, cyclosporin A; Me, median; Min-max, minimum-maximum values; MMF, mycophenolate mofetil; Pred, prednisone; Rapa, rapamycin; Tac, tacrolimus; $\overline{x}$ ± sD, mean ± standard deviation.

Table S3 Percentage of desmin-positive cells in the rat dorsolateral prostate in control (I) and experimental (II–VIII) groups

Group	Given drugs	Cells with weak expression of desmin (%)			Cells with moderate expression of desmin (%)			Cells with strong expression of desmin (%)
		Min–max	Me	$\overline{x}$± SD	Min–max	Me	$\overline{x}$± SD	Min–max	Me	$\overline{x}$± SD
I	–	29.2–60.7	51.5	50.3±7.7	17.5–48.3	31.3	31.1±6.7	0.9–22.9	4.4	5.9±4.9
II	Rapa, Tac, Pred	7.6–47.0	22.9	22.8*±6.8	17.4–39.4	26.9	27.0±5.5	16.8–69.0	44.2	45.7*±10.3
III	Rapa, CsA, Pred	32.4–69.9	47.8	48.9±9.1	7.4–33.0	17.2	17.9*±5.2	0.2–10.1	1.9	2.4±2.0
IV	Rapa, MMF, Pred	36.6–69.9	52.1	52.2±7.7	1.2–23.0	11.3	11.9*±4.5	0.1–6.6	1.1	1.5*± 1.4
V	CsA, MMF, Pred	11.1–42.3	28.5	27.3*±7.9	25.6–56.1	41.0	41.2*±6.8	11.6–43.8	27.7	27.8*±7.8
VI	CsA, MMF, Pred/Rapa	36.4–67.1	52.1	52.2a±6.4	13.8–43.2	33.3	32.9a±6.3	0.6–18.7	6.7	7.2a±3.7
VII	Tac, MMF, Pred	15.0–39.6	26.1	26.4*±6.7	34.1–58.1	48.7	47.4*±5.9	9.2–36.2	22.7	23.3*±7.0
VIII	Tac, MMF, Pred/Rapa	14.7–55.1	30.5	32.6*±11.8	20.4–58.0	36.7	38.8a,*±9.6	5.4–37.6	21.9	22.6*±9.2

Notes:

* P<0.05 vs control.

a Groups with the conversion of the treatment to Rapa, significantly different (P<0.05) vs the groups without Rapa (VI vs V and VIII vs VII).

Abbreviations: CsA, cyclosporin A; Me, median; Min-max, minimum-maximum values; MMF, mycophenolate mofetil; Rapa, rapamycin; Pred, prednisone; Tac, tacrolimus; $\overline{x}$ ± SD, mean ± standard deviation.