Effects of Anti-CD40L Monoclonal Antibody on Rejection of Rat Pancreatic Islet Xenografts_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

ZHANG Jian ¹ , CHEN Guihua ¹ , WENG Jianping ² , YANG Yang ¹ , LI Hua ¹ , WANG Genshu ¹

1. Liver Transplantation Center, The Third Affiliated Hospital， Sun Yat-sen University, Guangzhou 510630, China;;
2. Department of Endocrinology， The First Affiliated Hospital， Sun Yat-sen University, Guangzhou 510080, China;

Corresponding author：

Keywords：

Pancreatic islet xenografts; 　　Diabetes mellitus; 　　Immune tolerance; 　　Anti-CD40L monoclonal antibody

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Objective To study the effect of anti-CD40L monoclonal antibody on the rejection of rat pancreatic islet xenografts and its mechanism. Methods The animal models of human-rat pancreatic islet xenografts were established and were treated with anti-CD40L monoclonal antibody. The levels of blood glucose of transplantation rats were measured and the survival of grafts and transplantation rats were observed after transplantation. The morphological changes of grafts were observed and the levels of cytokines (IL-2 and TNF-α) were quantified by ELISA. Results ①Level of blood glucose in all the rats with diabetes decreased to normal on day (2.3±0.2) after transplantation. The average level blood glucose of control group began to increase on day (8.1±0.6), while the treatment group began to increase on day (18.5±1.2) after transplantation, which was significantly postponed compared with control respectively (P＜0.01). ②Grafts of treatment group and control group survived for (22±8.2) and (10±2.1) days respectively. Survival of grafts in treatment group was significant longer than that in control group (P＜0.01). ③Survival of transplantation rats were (35±6.5) and (21±5.7) days in treatment group and control group respectively. The survival of transplantation rats in treatment group was significant longer than that in control group (P＜0.05). ④Levels of serum IL-2 and TNF-α in control group increased dramatically within (3.2±0.3) days and reached peak within (7.3±0.5) days after transplantation, which were significantly higher than those measured before transplantation (P＜0.01); While in treatment group, the levels of serum IL-2 and TNF-α began to increase on day (22.6±1.7) after transplantation, and reached peak on day (28.5±2.2), which was significantly postponed than those in control group (P＜0.01). Conclusion Anti-CD40L monoclonal antibody can inhibit the rejection of rat pancreatic islet xenografts and prolong the survival time of transplantation rats and grafts.

Citation： ZHANG Jian,CHEN Guihua,WENG Jianping,YANG Yang,LI Hua,WANG Genshu. Effects of Anti-CD40L Monoclonal Antibody on Rejection of Rat Pancreatic Islet Xenografts. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2008, 15(5): 329-332. doi: Copy

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11.	Mai G, Bucher P, Morel P, et al. Anti-CD154 mAb treatment but not recipient CD154 deficiency leads to long-term survival of xenogeneic islet grafts [Ｊ]. Am J Transplant, 2005; 5(5)∶1021.
12.	Bigenzahn S, Blaha P, Koporc Z, et al. The role of non-deletional tolerance mechanisms in a murine model of mixed chimerism with costimulation blockade [Ｊ]. Am J Transplant, 2005; 5(6)∶1237.
13.	Larsen CP, Alexander DZ, Hollenbaugh D， et al. CD40-gp39 interactions play a critical role during allograft rejection. Suppression of allograft rejection by blockade of the CD40-gp39 pathway [Ｊ]. Transplantation, 1996; 61(1)∶4.
14.	Yamada And A, Sayegh MH. The CD154-CD40 costimulatory pathway in transplantation [Ｊ], Transplantation, 2002; 73(1 Suppl)∶S36.
15.	Nathan MJ, Mold JE, Wood SC, et al. Requirement for donor and recipient CD40 expression in cardiac allograft rejection: induction of Th1 responses and influence of donor-derived dendritic cells [Ｊ]. J Immunol, 2004; 172(11)∶6626.

1. Mirenda V, Golshayan D, Read J, et al. Achieving permanent survival of islet xenografts by independent manipulation of direct and indirect T-cell responses [Ｊ]. Diabetes, 2005; 54(4)∶1048.
2. Fernandes JR, Duvivier-Kali VF, Keegan M, et al. Transplantation of islets transduced with CTLA4-Ig and TGFbeta using adenovirus and lentivirus vectors [Ｊ]. Transpl Immunol, 2004; 13(3)∶191.
3. Nanji SA, Hancock WW, Anderson CC, et al. Multiple combination therapies involving blockade of ICOS/B7RP-1 costimulation facilitate long-term islet allograft surviva [Ｊ]. Am J Transplant, 2004; 4(4)∶526.
4. Gainer AL, Korbutt GS, Rajotte RV, et al. Expression of CTLA4-Ig by biolistically transfected mouse islets promotes islet allograft survival [Ｊ]. Transplantation, 1997; 63(7)∶1017.
5. Safley SA, Kapp LM, Tucker-Burden C, et al. Inhibition of cellular immune responses to encapsulated porcine islet xenografts by simultaneous blockade of two different costimulatory pathways [Ｊ]. Transplantation, 2005; 79(4)∶409.
6. Adams AB, Shirasugi N, Jones TR, et al. Development of a chimeric anti-CD40 monoclonal antibody that synergizes with LEA29Y to prolong islet allograft survival [Ｊ]. J Immunol, 2005; 174(1)∶542.
7. 赵高平，周总光. B7-CD28/CTLA4共刺激通路与胰岛移植 [Ｊ]. 中国普外基础与临床杂志, 2002; 9（6）∶442.
8. Sun Y, Peng D, Lecanda J, et al. In vivo gene transfer of CD40 ligand into colon cancer cells induces local production of cytokines and chemokines, tumor eradication and protective antitumor immunity [Ｊ]. Gene Ther, 2000; 7(17)∶1467.
9. Guillonneau C, Aubry V, Renaudin K, et al. Inhibition of chronic rejection and development of tolerogenic T cells after ICOS-ICOSL and CD40-CD40L co-stimulation blockade [Ｊ]. Transplantation, 2005; 80(4)∶546.
10. Brenner MJ, Mackinnon SE, Rickman SR, et al. FK506 and anti-CD40 ligand in peripheral nerve allotransplantation [Ｊ]. Restor Neurol Neurosci, 2005; 23(3-4)∶237.
11. Mai G, Bucher P, Morel P, et al. Anti-CD154 mAb treatment but not recipient CD154 deficiency leads to long-term survival of xenogeneic islet grafts [Ｊ]. Am J Transplant, 2005; 5(5)∶1021.
12. Bigenzahn S, Blaha P, Koporc Z, et al. The role of non-deletional tolerance mechanisms in a murine model of mixed chimerism with costimulation blockade [Ｊ]. Am J Transplant, 2005; 5(6)∶1237.
13. Larsen CP, Alexander DZ, Hollenbaugh D， et al. CD40-gp39 interactions play a critical role during allograft rejection. Suppression of allograft rejection by blockade of the CD40-gp39 pathway [Ｊ]. Transplantation, 1996; 61(1)∶4.
14. Yamada And A, Sayegh MH. The CD154-CD40 costimulatory pathway in transplantation [Ｊ], Transplantation, 2002; 73(1 Suppl)∶S36.
15. Nathan MJ, Mold JE, Wood SC, et al. Requirement for donor and recipient CD40 expression in cardiac allograft rejection: induction of Th1 responses and influence of donor-derived dendritic cells [Ｊ]. J Immunol, 2004; 172(11)∶6626.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Effects of Anti-CD40L Monoclonal Antibody on Rejection of Rat Pancreatic Islet Xenografts

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