Local Inflammatory Response Around Diffusion Chambers Containing Xenografts

Abstract

Immunoisolation of xenogeneic pancreatic islets within membrane-bound devices has been proposed as an approach to cure diabetes. We examined the local response to implanted xenografts and allografts in comparison with isografts in diffusion chambers with 0.4-microm pore membranes when implanted into epididymal fat pads of rats. These membranes prevented host cell entry into the device but did not prevent passage of large molecules such as IgG and IgM. Well-differentiated allogeneic tissues (Sprague-Dawley rat embryonic lung implanted into Lewis rats) survived for 1 year when implanted in intact devices, but similar tissues were destroyed within 3 weeks when implanted within devices with holes poked in the membrane to allow host cell contact. In contrast, xenografts (CF1 mouse embryonic lung implanted into Lewis rats) were destroyed within 3 weeks even when implanted in devices with intact membranes. The death of the xenogeneic tissues was accompanied by a severe local accumulation of inflammatory cells and a decrease in local vascularization. When isogeneic tissues (Lewis rat embryonic lung implanted in Lewis rats) were mixed with xenogeneic tissues, a local inflammatory response occurred and both iso- and xenogeneic tissues were destroyed within 5 weeks. These results suggest the possibility that xenografts are killed by local accumulation of inflammatory cells, perhaps mediated by the release of antigens from the tissues within the device and presentation by an indirect pathway. The observation that the local response to xenografts is sufficient to kill isografts complicates issues of immunoprotection, suggesting that successful immunoisolation will require membranes that not only provide protection of the encapsulated tissues from the host immune system but also have properties that diminish the release of xenogeneic antigens.

Transplantation of macroencapsulated human islets within the bioartificial pancreas βAir to patients with type 1 diabetes mellitus

“…The βAir device would tentatively benefit from increasing its surface‐to‐volume ratio; however, with the limitations that the device will still have to keep dimensions reasonable for clinical application. Notably, a membrane with pore sizes as large as 0.45 μm seems able to control islet allograft rejection in rodent models,5, 18, 19 as well as in this and a previous clinical trial,20 ie, preventing cell‐to‐cell contact between donor and recipient cells seems sufficient to prevent HLA immunization and allograft rejection. Implantation of the islets in an alginate gel potentially also impairs diffusion.…”

A novel macroencapsulating immunoisolatory device: the preparation and properties of nanomat-reinforced amphiphilic co-networks deposited on perforated metal scaffold

“…is relatively easy to perform, the encapsulated tissue is easily implanted by syringes, and the method yields excellent surface/volume ratios for transport kinetics. Experiments in immunoisolation have demonstrated that encapsulated syngeneic cells implanted into rodents do quite well, but encapsulated allogeneic cells have a short survival period, and xenografts are destroyed even faster (Brauker et al 1996;Loudovaris et al 1992).…”

In vivo Studies on Insulin Permeability of an Immunoisolation Device Intended for Islet Transplantation Using the Microdialysis Technique

“…At this time, the amount of insulin recovered and the kinetics have almost fully returned to normal and are not significantly different from those in the control group. This is a rather unexpected finding, since several publications report increasing fibrosis during the first months after implantation [19][20][21][22]. A possible explanation could be changes in, or even degradation of, the membrane material.…”

“…The in vivo diffusion barrier will depend partly on the immunoisolating membrane but also on the tissue reaction in the recipient. The development of an avascular foreing body reaction around an implant, a common problem in the fields of both macro-and microencapsulation, will hinder the survival and function of the encapsulated graft, while a well-vascularized surrounding tissue should be favorable [19][20][21][22].…”