Nanomedicine, Volume IIA: Biocompatibility
© 2003 Robert A. Freitas Jr. All Rights Reserved.
Robert A. Freitas Jr., Nanomedicine, Volume IIA: Biocompatibility, Landes Bioscience, Georgetown, TX, 2003
22.214.171.124 Immune Privilege
Immune privilege [425-434], first described 130 years ago , protects tissue grafted to certain sites from rejection. Medawar’s original explanation for this phenomenon  – that immune privilege was just immune ignorance, with privileged sites isolated behind blood-tissue barriers lacking lymphatic drainage, and with antigenic material (trapped within these isolated sites) remaining invisible to the immune system – is now known to be incorrect. It has since been found that foreign tissues in privileged sites could eventually evoke antigen-specific systemic immunity  and that certain privileged sites (such as the testis) had extensive efferent lymphatic pathways . Rather than immune ignorance, the systemic immune apparatus recognizes antigens in privileged sites and cooperates to create and sustain a graft-friendly environment . Medical nanorobot engineers may be able to borrow some of nature’s techniques and convince the body’s immune system that resident nanorobots or implanted nanorobotic organs possess immune privilege and thus should not be attacked.
There are two distinct loci of immune privilege: (1) privileged sites (the best example being the fetus) and (2) privileged tissues. Immune-privileged sites and tissues include  the eye (anterior chamber, cornea, and retina) , brain [428, 789], hair follicles [790, 791], cartilages, liver [426, 429], adrenal cortex, uterus (pregnant) and placenta , ovary and testis [425, 427, 456], prostate , and tumors [433, 441]. Immune privilege is biologically necessary for the success of pregnancy . Immune privilege in the anterior chamber of the eye is critical to the avoidance of stromal keratitis, a blinding disease of the cornea accompanying ocular infection with HSV-1. In mice, the incidence and severity of HSV-1 keratitis rises dramatically in eyes where privilege has been lost . Orthotopic corneal allografts are the most successful of all solid-organ transplants in humans because the eye is a privileged site and the cornea is a privileged tissue . Corneal grafts placed in eyes that have lost immune privilege suffer acute rejection .
Immune-privileged sites are regions of the body where allogeneic or xenogeneic grafts of foreign tissue enjoy prolonged, even indefinite, survival relative to nonprivileged sites. These are regions in the body where the immune system appears not to function . Infectious organisms or tumor cells inserted into immune-privileged sites do not elicit destructive or protective immunity [441, 442]. The eye is an example of a privileged site, where even minor episodes of inflammation could result in impaired vision or even blindness if the inflammation proceeds unchecked . HSV-1 virus injected directly into the anterior chamber of mouse eyes induced an immediate infiltration of neutrophils and lymphocytes, but extensive apoptosis (Section 10.4.1.1) was observed in infiltrating immune cells 24 hours after infection in animals having functional CD95 (aka. Fas or APO-1) receptors and CD95L (aka. FasL) ligand expression . By expressing CD95L, the eye directly kills activated immune cells that might invade the globe and destroy vision . CD95L expression in the testis (another privileged site) may perform a similar function [443, 444]. As summarized by Streilein , privileged sites incorporate multiple additional features allowing them to accept foreign grafts. These features include: (1) blood-tissue barriers (for eye, brain); (2) absence of efferent lymphatics (eye); (3) direct tissue fluid drainage into the blood (eye, brain); (4) functional integrity of the spleen (eye) ; (5) establishment of a potent immunosuppressive microenvironment  containing growth factors such as TGF-beta (eye, brain, placenta, testis)  and neuropeptides (eye) [448, 449]; and (6) soluble and membrane-bound inhibitors of complement activation and fixation (anterior chamber of eye) [450-451]. Antigenic materials placed in privileged sites evoke a state of deviant systemic immunity in which the usual mediators of immunogenic inflammation (e.g., delayed hypersensitivity T cells, complement-fixing antibodies) are curtailed, and other mediators (e.g., cytotoxic T cells, noncomplement-fixing IgG antibodies) are enhanced [452-454]. For example, antigen injected into the eye is picked up locally by intraocular dendritic cells, which then migrate via the blood to the splenic white pulp where antigen-specific regulatory and effector T cells are activated . At least four pathways are known by which immune privilege can lead to T-cell tolerance : clonal deletion , clonal anergy, immune deviation [437, 442, 447, 449], and T-cell suppression .
Immune-privileged tissues resist immune rejection when grafted into conventional (nonprivileged) sites. For example, constitutive expression of CD95L on the Sertoli cells of a testis graft triggers apoptosis in the recipient’s CD95+ antigen-activated T cells that are challenging the graft . Myoblasts (muscle cells) genetically engineered to express FasL can protect neighboring transplanted islet cells by inducing apoptosis in visiting T cells for more than 80 days in mice , although the altered myoblasts evidently stimulate an inflammatory response that eventually destroys them . CD95L-coated tissues (eye, testis, tumor cells) generally stay free of patrolling immune cells. However, Chen et al  have noted that while surface-expressed CD95L triggers apoptosis in T lymphocytes [458-461], it also stimulates neutrophils and other polymorphonuclear leukocytes. This stimulation may then be inhibited by the local presence of TGF-beta – together, CD95L and TGF-beta promote lymphocyte clonal deletion and suppress inflammation . Privileged tissues also are often characterized  by intratissue structural barriers such as extensive tight junctions among parenchymal cells (Sertoli cells, retinal pigment epithelium); elaborate surface expression of hyaluronic acid (placenta, trabecular meshwork of the eye); reduced or absent expression of MHC class I and class II molecules (brain, eye, placenta); expression of class Ib molecules (placenta) [433, 462]; release of class I molecules (liver) ; secretion of immunosuppressive cytokines (eye) [464-466] and corticosteroids (gonads); and fetal-like fibroblasts (gingival oral mucosa) .
Another instance of immune-privileged cells is the embryo, whose developing cells in the placenta manufacture an enzyme known as indoleamine 2,3-dioxygenase (IDO). IDO destroys tryptophan, an amino acid needed by maternal T cells (human cells cannot make their own tryptophan). This localized cell-induced nutrient depletion is believed to suppress the activity of maternal T cells that would otherwise make their way through the placenta and attack the fetal blood supply . Other studies have shown that certain macrophages, induced to express IDO in response to interferon-gamma from activating T cells, inhibit T cell proliferation in vitro by rapidly consuming tryptophan [469-471]. Amniotic membrane, a related privileged tissue that is fetal in origin and multipotential, lies between mother and baby and reacts with neither. It can be transplanted between species and still survive without the need for immunosuppression. In experimental studies, human amnion has been used to resurface rabbit knee joints [472-474] and can be useful in ocular [475-481] and other [482-488] transplantation procedures. Fibroblasts, which do not constitutively express HLA class II molecules, cannot induce the formation of required helper T cells and thus stimulate no rejection response when transplanted between hosts . Human stem cells were originally believed to provoke no immunogenic reaction because they are not differentiated. However, recent results by Drukker et al  found very low but consistent expression of MHC class I molecules even on undifferentiated human embryonic stem cells. As the cells differentiated, they produced higher levels of the proteins – probably high enough to trigger an immune reaction  and to be rejected upon transplantation . (Even though embryonic stem cells aren’t invisible to the immune system, these cells could be genetically engineered so as not to express MHC proteins, or nuclear transfer techniques might be used to create genetically matched stem cells for individual patients .)
Last updated on 30 April 2004