Intensity and mechanisms of in vitro xenorecognition of adult pig pancreatic islet cells by CD 4 + and CD 8 + lymphocytes from Type I diabetic or healthy subjects

Lalain, Sandrine; Chaillous, Lucy; Gouin, E.; P, Sai

doi:10.1007/s001250051159

Cited by 18 publications

(18 citation statements)

References 14 publications

(17 reference statements)

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“…Previous studies have shown this to be a strong immune response that is difficult to suppress (5,(32)(33)(34). It is different mechanistically from allograft rejection in that CD8 ϩ T cells are not involved, and more macrophage-mediated destruction occurs at early time points (35,36).…”

Section: Discussionmentioning

confidence: 96%

T Cell-Activated Macrophages Are Capable of Both Recognition and Rejection of Pancreatic Islet Xenografts

Hawthorne

Lehnert

et al. 2003

The Journal of Immunology

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Macrophages have been proposed as the major effector cell in T cell-mediated xenograft rejection. To determine their role in this response, NOD-SCID mice were transplanted with fetal pig pancreas (FPP) before reconstitution with CD4+ T cells from BALB/c mice. Twelve days after CD4+ T cell reconstitution, purified macrophages (depleted of T cells) were isolated from CD4+ T cell-reconstituted FPP recipient mice and adoptively transferred to their nonreconstituted counterparts. After adoptive macrophage transfer, FPP recipient mice transferred with macrophages from CD4+ T cell-reconstituted mice demonstrated xenograft destruction along with massive macrophage infiltration at day 4 and complete graft destruction at day 8 postmacrophage transfer. By contrast, FPP recipients that received macrophages from nonreconstituted mice showed intact FPP xenografts with few infiltrating macrophages at both days 4 and 8 after macrophage transfer. The graft-infiltrating macrophages showed increased expression of their activation markers. Depletion of endogenous macrophages or any remaining CD4+ T cells did not delay graft rejection in the macrophage-transferred FPP recipients, whereas depletion of transferred macrophages with clodronate liposomes prevented graft rejection. Our results show that macrophages primed by FPP and activated by CD4+ T cells were attracted from the peripheral circulation and were capable of specific targeting and destruction of FPP xenografts. This suggests that in xenograft rejection, there are macrophage-specific recognition and targeting signals that are independent of those received by T cells.

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Section: Discussionmentioning

confidence: 96%

T Cell-Activated Macrophages Are Capable of Both Recognition and Rejection of Pancreatic Islet Xenografts

Hawthorne

Lehnert

et al. 2003

The Journal of Immunology

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“…The primers amplified a 7.2 kb fragment from all PERV-A, -B, or -C sequences. 6 (Pharmacia Biotech, Uppsala, Sweden). Thirteen microlitres of cDNA templates were amplified with pol, gag, env-A, env-B or env-C primers in the conditions described above.…”

Section: Methodsmentioning

confidence: 99%

“…The primers used for PCR amplification of PERV sequences or pig mt DNA were synthesised by the Life Tech-During xenograft, there is a risk of transmitting infectious agents from pig to man. The risk of conventional zoonosis led us to isolate islets from specific pathogen-free (SPF) pigs [1,2,3,4,5,6,7,8]. However, there is also a risk of transmitting porcine endogenous retroviruses (PERV) [9,10,11,12].…”

Section: Pcr-derived Monitoring Of Perv Infection and Microchimerism mentioning

confidence: 99%

Microchimerism and transmission of porcine endogenous retrovirus from a pig cell line or specific pathogen-free pig islets to mouse tissues and human cells during xenografts in nude mice

et al. 2002

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Aims/hypothesis. Pig islets could transmit porcine endogenous retroviruses (PERV) to diabetic patients. Our previous work showed that pig islets expressed low levels of PERV mRNA and were not likely to transmit PERV to human cells in vitro. The real risk of infection during pig tissue xenografts can only be evaluated by in vivo experiments. Methods. Nude mice bearing tumours containing human 293 cells were grafted with specific pathogenfree pig islets or PERV-producing pig PK15 cells to determine whether pig cells could transmit PERV to mouse and human cells in vivo. Infection was monitored by PCR, long PCR, RT-PCR and long RT-PCR. As detection of PERV sequences could be due to the presence of residual pig cells, we looked for pig mitochondrial (mt) DNA. Quantitative PCR for PERV and pig mt DNA was done to compare the PERV-topig mt (P-to-M) ratio of each sample with the reference ratio for grafted pig cells. Results. Among 78 mouse tissues from PK15-grafted mice, 54 and 72 were positive for gag and pig mt DNA, respectively. Human tumours developed in these mice were positive for PERV (78%) and pig mt (89%). The P-to-M ratios for mouse tissues and PERV-positive human tumours from PK15-grafted mice were higher than the ratio in PK15 cells. Among 41 tissues from pig islet cell-grafted mice, 7 were positive for PERV (3 lymph nodes, 1 kidney, 2 salivary glands, 1 ovary), and 14 were positive for pig mt DNA. Three of these samples (1 lymph node, 1 kidney and 1 salivary gland) were positive for gag DNA, but negative for pig mt DNA. One human tumour in these mice was positive for PERV DNA. P-to-M reference ratio in grafted islet cells was 0.05±0.03. The three PERVpositive lymph nodes contained 78 gag/3 mt copies (P-to-M: 26), 101 gag/3 mt copies (P-to-M: 34), and 4 gag/0 mt copies. The two PERV-positive salivary glands contained 14 gag/1 mt copies, and 28 gag/0 mt copies. The ovary and the kidney contained 46 gag/ 3 mt and 69 gag/0 mt copies, respectively. The PERV-positive human tumour contained 47 gag/3 mt copies. Conclusions/interpretation. Microchimerism and PERV transmission were frequently observed in both mouse and human tissues during grafting of pig PK15 cells into nude mice bearing human tumours, and sometimes during pig islet xenograft in this model. This strengthens the notion that there is a risk of transmitting PERV during pig islet xenograft. [Diabetologia (2002) 45:914-923] Keywords Xenograft, pig endogenous retrovirus, pig islet cell, PK15 cells, specific pathogen free pig, human cells, mouse. vided by E. Gouin (Ploufragan and Nantes, France) from Large-White SPF pigs (80-120 kg), aged 20 weeks, as previously described [1,2]. Pancreases were removed in betadine solution and inflated with 100 ml ice-cold sterile modified University of Wisconsin (mUW) solution and transported in mUW. Pancreases were then inflated again with 0.5 ml/g of mUW solution containing 2 mg/ml Liberase (Roche Diagnostics, Meylan, France) and placed in a digestion chamber filled with mUW solution kept at 36°C. Crude isle...

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“…Murray et al demonstrated that islet rejection likely occurs via a CD4+ T cell-directed response, with NK cell and CD8+ T cell-mediated injury of the xenograft not contributing to islet loss [37]. Additionally, a study by Lalain et al [39]. examined the adaptive immune response in vitro to adult porcine islets in type 1 diabetic and healthy human subjects.…”

Section: Adaptive Immune Responsementioning

confidence: 99%

“…examined the adaptive immune response in vitro to adult porcine islets in type 1 diabetic and healthy human subjects. It was shown that the immune response to porcine islet cells involves dominantly CD4+ T cells activated through the indirect pathway, as well as CD8+ T cells activated through the direct pathway [39].…”

Section: Adaptive Immune Responsementioning

confidence: 99%

Immune Response Associated with Islet Xenotransplantation in Small and Large Animal Models

Croden¹,

Huang²,

Rayat³

2017

Xenotransplantation - New Insights

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This chapter will review studies that examine the immune response to porcine neonatal pancreatic cell clusters (NPCC) in small and large animal models; specifically, the immune mechanisms that lead to the rejection of transplanted islet cells in mice, nonhuman primates, and humans will be discussed. In addition, current research on the in vitro and in vivo human immune responses to porcine NPCC is also included. Research into the immune responses that lead to islet cell death posttransplant allows for further understanding of how to better protect transplanted porcine NPCC in humans. Furthermore, this chapter will examine immune-related strategies that have shown to extend the life and/or function of porcine NPCC in vitro and in vivo, including techniques that work to modulate the immune system of the islet cell donor and/or the recipient. Finally, this chapter will identify future areas of research that have yet to be examined extensively in the literature, mostly pertaining to the human immune response to porcine NPCC in the clinical setting.

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Intensity and mechanisms of in vitro xenorecognition of adult pig pancreatic islet cells by CD 4 + and CD 8 + lymphocytes from Type I diabetic or healthy subjects

Cited by 18 publications

References 14 publications

T Cell-Activated Macrophages Are Capable of Both Recognition and Rejection of Pancreatic Islet Xenografts

T Cell-Activated Macrophages Are Capable of Both Recognition and Rejection of Pancreatic Islet Xenografts

Microchimerism and transmission of porcine endogenous retrovirus from a pig cell line or specific pathogen-free pig islets to mouse tissues and human cells during xenografts in nude mice

Immune Response Associated with Islet Xenotransplantation in Small and Large Animal Models

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