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A Method for Murine Islet Isolation and Subcapsular Kidney Transplantation
Published on: April 13, 2011
Pig islet xenograft rejection is markedly delayed in macrophage-depleted mice: a study in streptozotocin diabetic
1Department of Transplantation Surgery, Huddinge Hospital, Karolinska Institute, Stockholm, Sweden. guoshengwu@hotmail.com
Abstract:
The present study aimed to evaluate the effect of depletion of macrophages and/or natural killer (NK) cells on islet xenograft rejection in the pig-to-mouse model. Five microliters (4,000 to 5,000 IEQ, islet equivalents) of adult pig islets were transplanted under the renal capsule of C57BL/6 mice with streptozotocin-induced diabetes. Macrophages were depleted by injection of liposome-encapsulated dichloromethylene diphosphonate (Lip-Cl2MDP) intraperitoneally (i.p.) at a dose of 100 microl/ 10 g body weight (BW) 2 days before transplantation, and 50 microl/10 g BW weekly thereafter. NK cells were depleted by injection of the monoclonal antibody NK 1.1 (anti-NK 1.1 mAb) i.p. at a dose of 100 microg/mouse 1 day before transplantation, and then 25 microg per week thereafter. Islet graft survival was monitored by daily measurements of blood glucose. Graft survival was 8 +/- 1.2 days in untreated controls, 9 +/- 1.0 days with anti-NK 1.1 mAb alone, 22 +/- 4.9 days with Lip-Cl2MDP alone (P<0.01 vs. controls), and 26 +/- 3.8 days with Lip-Cl2MDP plus anti-NK 1.1 mAb (P<0.01 vs. controls). In the last group, two of six animals were killed with functioning grafts 30 days after transplantation. In untreated controls, rejected xenografts were heavily infiltrated by F4/80+ macrophages and CD3+T cells. In Lip-Cl2MDP-treated groups, the number of F4/80+ macrophages was markedly reduced. On the periphery of xenografts, a small number of CD3+T cells were observed. In conclusion, our results suggest that strategies targeting macrophages may facilitate islet xenograft survival. A role for NK cells cannot be excluded, but appears to be of minor importance.
Insights
Depleting macrophages significantly prolonged pig islet xenograft survival in mice, suggesting targeting macrophages is a promising strategy for xenotransplantation. Natural killer cells played a minor role.
Area of Science:
- Transplantation Biology
- Immunology
- Xenotransplantation Research
Background:
- Islet xenotransplantation offers a potential solution for diabetes.
- Understanding immune rejection mechanisms is crucial for xenograft survival.
Purpose of the Study:
- To investigate the impact of macrophage and natural killer (NK) cell depletion on pig islet xenograft rejection in a mouse model.
- To evaluate the efficacy of targeting specific immune cells in preventing xenograft failure.
Main Methods:
- Pig islets were transplanted into streptozotocin-induced diabetic C57BL/6 mice.
- Macrophages were depleted using liposome-encapsulated dichloromethylene diphosphonate (Lip-Cl2MDP).
- NK cells were depleted using anti-NK 1.1 monoclonal antibody (mAb).
- Graft survival was monitored by blood glucose levels.
Main Results:
- Macrophage depletion alone (Lip-Cl2MDP) significantly extended graft survival to 22 days (P<0.01).
- Combined depletion of macrophages and NK cells resulted in prolonged survival up to 26 days (P<0.01), with two grafts functioning at 30 days.
- Reduced macrophage infiltration was observed in xenografts following Lip-Cl2MDP treatment.
Conclusions:
- Targeting macrophages represents a viable strategy to enhance islet xenograft survival.
- While NK cells may play a role, their depletion appears less critical than macrophage depletion for xenograft success in this model.
