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Effect of alemtuzumab on intestinal intraepithelial lymphocytes and intestinal barrier function in cynomolgus model.

Qu LL, Lyu YQ, Jiang HT, Shan T, Zhang JB, Li QR, Li JS - Chin. Med. J. (2015)

Bottom Line: The numbers of IELs were decreased significantly on day 9 after treatment compared with the control group (0.35 ± 0.07 × 10 8 and 1.35 ± 0.09 × 10 8 , respectively; P < 0.05) and were not fully restored until day 70 after treatment.There were significant differences among four groups considering IELs subtypes.Moreover, the concentration of D-lactate and endotoxin was also increased significantly on day 9 after treatment.

View Article: PubMed Central - PubMed

Affiliation: Department of General Surgery, Institute of General Surgery, Jinling Hospital, Nanjing, Jiangsu 210002, China.

ABSTRACT

Background: Alemtuzumab has been used in organ transplantation and a variety of hematologic malignancies (especially for the treatment of B-cell chronic lymphocytic leukemia). However, serious infectious complications frequently occur after treatment. The reason for increased infections postalemtuzumab treatment is unknown at this stage. We explore the effect of alemtuzumab on intestinal intraepithelial lymphocytes (IELs) and intestinal barrier function in cynomolgus model to explain the reason of infection following alemtuzumab treatment.

Methods: Twelve male cynomolguses were randomly assigned to either a treatment or control group. The treatment group received alemtuzumab (3 mg/kg, intravenous injection) while the control group received the same volume of physiological saline. Intestinal IELs were isolated from the control group and the treatment group (on day 9, 35, and 70 after treatment) for counting and flow cytometric analysis. Moreover, intestinal permeability was monitored by enzymatic spectrophotometric technique and enzyme-linked immunosorbent assay.

Results: The numbers of IELs were decreased significantly on day 9 after treatment compared with the control group (0.35 ± 0.07 × 10 8 and 1.35 ± 0.09 × 10 8 , respectively; P < 0.05) and were not fully restored until day 70 after treatment. There were significant differences among four groups considering IELs subtypes. In addition, the proportion of apoptotic IELs after alemtuzumab treatment was significantly higher than in the control group (22.01 ± 3.67 and 6.01 ± 1.42, respectively; P < 0.05). Moreover, the concentration of D-lactate and endotoxin was also increased significantly on day 9 after treatment.

Conclusions: Alemtuzumab treatment depletes lymphocytes in the peripheral blood and intestine of cynomolgus model. The induction of apoptosis is an important mechanism of lymphocyte depletion after alemtuzumab treatment. Notably, intestinal barrier function may be disrupted after alemtuzumab treatment.

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Modulation of tight junctions (TJs) structure after alemtuzumab treatment. In controls, TJ and desmosome displayed an intact structure. On the 9th and the 35th day after treatment, alteration of TJ ultrastructure was observed, and desmosome disappeared. The TJ structure recovered on the 70th day after treatment. Arrows: TJs; arrowheads: Desmosomes (Original magnification × 20000).
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Figure 5: Modulation of tight junctions (TJs) structure after alemtuzumab treatment. In controls, TJ and desmosome displayed an intact structure. On the 9th and the 35th day after treatment, alteration of TJ ultrastructure was observed, and desmosome disappeared. The TJ structure recovered on the 70th day after treatment. Arrows: TJs; arrowheads: Desmosomes (Original magnification × 20000).

Mentions: Tight junctions (TJs) play an important regulatory role in barrier function. To assess the effects of alemtuzumab on TJ ultrastructure, TEM was performed on the colon. It was showed in Figure 5, that TEM of the colon revealed an intact TJ structure in cynomolgus of the control group. The ultrastructure of TJs was altered in animals after intravenously guttae with alemtuzumab for 9 and 35 days. The desmosome disappeared, and TJ membrane fusions were lost. It indicated that the normal TJ morphology was disrupted after treatment. On the 70th day after treatment, the desmosome and TJ membrane fusions reemerged, which indicated that TJ has recovered [Figure 5].


Effect of alemtuzumab on intestinal intraepithelial lymphocytes and intestinal barrier function in cynomolgus model.

Qu LL, Lyu YQ, Jiang HT, Shan T, Zhang JB, Li QR, Li JS - Chin. Med. J. (2015)

Modulation of tight junctions (TJs) structure after alemtuzumab treatment. In controls, TJ and desmosome displayed an intact structure. On the 9th and the 35th day after treatment, alteration of TJ ultrastructure was observed, and desmosome disappeared. The TJ structure recovered on the 70th day after treatment. Arrows: TJs; arrowheads: Desmosomes (Original magnification × 20000).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4834783&req=5

Figure 5: Modulation of tight junctions (TJs) structure after alemtuzumab treatment. In controls, TJ and desmosome displayed an intact structure. On the 9th and the 35th day after treatment, alteration of TJ ultrastructure was observed, and desmosome disappeared. The TJ structure recovered on the 70th day after treatment. Arrows: TJs; arrowheads: Desmosomes (Original magnification × 20000).
Mentions: Tight junctions (TJs) play an important regulatory role in barrier function. To assess the effects of alemtuzumab on TJ ultrastructure, TEM was performed on the colon. It was showed in Figure 5, that TEM of the colon revealed an intact TJ structure in cynomolgus of the control group. The ultrastructure of TJs was altered in animals after intravenously guttae with alemtuzumab for 9 and 35 days. The desmosome disappeared, and TJ membrane fusions were lost. It indicated that the normal TJ morphology was disrupted after treatment. On the 70th day after treatment, the desmosome and TJ membrane fusions reemerged, which indicated that TJ has recovered [Figure 5].

Bottom Line: The numbers of IELs were decreased significantly on day 9 after treatment compared with the control group (0.35 ± 0.07 × 10 8 and 1.35 ± 0.09 × 10 8 , respectively; P < 0.05) and were not fully restored until day 70 after treatment.There were significant differences among four groups considering IELs subtypes.Moreover, the concentration of D-lactate and endotoxin was also increased significantly on day 9 after treatment.

View Article: PubMed Central - PubMed

Affiliation: Department of General Surgery, Institute of General Surgery, Jinling Hospital, Nanjing, Jiangsu 210002, China.

ABSTRACT

Background: Alemtuzumab has been used in organ transplantation and a variety of hematologic malignancies (especially for the treatment of B-cell chronic lymphocytic leukemia). However, serious infectious complications frequently occur after treatment. The reason for increased infections postalemtuzumab treatment is unknown at this stage. We explore the effect of alemtuzumab on intestinal intraepithelial lymphocytes (IELs) and intestinal barrier function in cynomolgus model to explain the reason of infection following alemtuzumab treatment.

Methods: Twelve male cynomolguses were randomly assigned to either a treatment or control group. The treatment group received alemtuzumab (3 mg/kg, intravenous injection) while the control group received the same volume of physiological saline. Intestinal IELs were isolated from the control group and the treatment group (on day 9, 35, and 70 after treatment) for counting and flow cytometric analysis. Moreover, intestinal permeability was monitored by enzymatic spectrophotometric technique and enzyme-linked immunosorbent assay.

Results: The numbers of IELs were decreased significantly on day 9 after treatment compared with the control group (0.35 ± 0.07 × 10 8 and 1.35 ± 0.09 × 10 8 , respectively; P < 0.05) and were not fully restored until day 70 after treatment. There were significant differences among four groups considering IELs subtypes. In addition, the proportion of apoptotic IELs after alemtuzumab treatment was significantly higher than in the control group (22.01 ± 3.67 and 6.01 ± 1.42, respectively; P < 0.05). Moreover, the concentration of D-lactate and endotoxin was also increased significantly on day 9 after treatment.

Conclusions: Alemtuzumab treatment depletes lymphocytes in the peripheral blood and intestine of cynomolgus model. The induction of apoptosis is an important mechanism of lymphocyte depletion after alemtuzumab treatment. Notably, intestinal barrier function may be disrupted after alemtuzumab treatment.

Show MeSH
Related in: MedlinePlus