Biomedical subjects

Derry C Roopenian

Publications and source records attributed to Derry C Roopenian.

26 records · Page 2Linked to original sources

PubMed2003

An immunodominant minor histocompatibility alloantigen that initiates corneal allograft rejection.

BACKGROUND: Murine orthotopic corneal allografts experience immune privilege and have good survival as compared with skin allografts. However, privilege is not complete, and some grafts are still rejected. Unexpectedly, corneas expressing minor histocompatibility (H) alloantigens are rejected at a higher rate than major histocompatibility complex (MHC) disparate grafts. We hypothesize that certain immunodominant minor H alloantigens are extremely immunogenic when expressed in corneal tissue, terminate ocular immune privilege, and initiate corneal allograft rejection. METHODS AND RESULTS: Corneal allograft survival and the role of CD4+ T cells and CD8+ T cells were examined in corneal transplants that expressed genetically defined minor H3 alloantigens. The H3 locus contains at least two minor H genes. H3a is presented by MHC class I and recognized exclusively by CD8+ T cells. H3b is presented by class II and recognized exclusively by CD4+ T cells. Congenic strains that differ from C57BL/10 at (1) H3a, (2) H3b, or (3) H3a+H3b were used for orthotopic corneal and skin transplants. Donor corneas expressing either H3a or H3a+H3b experienced immune privilege and survived longer than skin allografts. By contrast, donor corneas expressing H3b (recognized by CD4+ T cells) experienced vigorous rejection and were eliminated faster than skin allografts. CONCLUSION: There are minor H alloantigens that terminate ocular immune privilege and initiate corneal allograft rejection. These minor H alloantigens are more immunogenic when expressed in corneal tissue than when they are expressed in skin allografts.

Animals↗

PubMed2003

The MHC class I-like IgG receptor controls perinatal IgG transport, IgG homeostasis, and fate of IgG-Fc-coupled drugs.

Abs of the IgG isotype are efficiently transported from mother to neonate and have an extended serum t(1/2) compared with Abs of other isotypes. Circumstantial evidence suggests that the MHC class I-related protein, the neonatal FcR (FcRn), is the FcR responsible for both in vivo functions. To understand the phenotypes imposed by FcRn, we produced and analyzed mice with a defective FcRn gene. The results provide direct evidence that perinatal IgG transport and protection of IgG from catabolism are mediated by FcRn, and that the latter function is key to IgG homeostasis, essential for generating a potent IgG response to foreign Ags, and the basis of enhanced efficacy of Fc-IgG-based therapeutics. FcRn is therefore a promising therapeutic target for enhancing protective humoral immunity, treating autoimmune disease, and improving drug efficacy.

Abatacept↗

PubMed2003

The major histocompatibility complex-related Fc receptor for IgG (FcRn) binds albumin and prolongs its lifespan.

The inverse relationship between serum albumin concentration and its half-life suggested to early workers that albumin would be protected from a catabolic fate by a receptor-mediated mechanism much like that proposed for IgG. We show here that albumin binds FcRn in a pH dependent fashion, that the lifespan of albumin is shortened in FcRn-deficient mice, and that the plasma albumin concentration of FcRn-deficient mice is less than half that of wild-type mice. These results affirm the hypothesis that the major histocompatibility complex-related Fc receptor protects albumin from degradation just as it does IgG, prolonging the half-lives of both.

Animals↗

PubMed2002

T cell knockout mice have diminished alveolar bone loss after oral infection with Porphyromonas gingivalis.

Periodontal diseases are chronic inflammatory diseases that can result in resorption of the alveolar bone of the jaw. We have developed a murine model in which alveolar bone loss is induced by oral infection with Porphyromonas gingivalis, an oral anaerobic bacterium associated with periodontal disease in humans. Here we compared a strain of immunocompetent mice (C57BL/6J) to the same strain of mice made T cell deficient by genetic deletion of the alpha chain of their T cell receptors (C57BL/6J-Tcra). T cell deficiency did not affect the ability of P. gingivalis to implant in the oral cavity. The two strains of mice had equal percentages of P. gingivalis among their cultivable anaerobes 7 weeks after infection. The same bacterial load led to much less bone resorption in the T cell deficient mice than in the immune normal mice, measured as either the number of sites with significant loss, or as the total amount of bone resorbed. T cell deficient mice lost bone at only three out of 14 measurement sites, compared with eight out of 14 sites in the wild-type mice. The total amount of bone lost was 70% less in the T cell deficient mice. T cell deficient mice had lower titers of P. gingivalis-specific IgG than the wild-type mice after oral infection did, but the same titers of specific IgA. Lower titers did not correlate with greater bone loss. Antigen-activated T lymphocytes are known to induce osteoclastogenesis; here we demonstrate that T cell deletion decreases the amount of alveolar bone loss induced by infection of the murine oral cavity.

Alveolar Bone Loss↗

PubMed2002

Real-time T-cell profiling identifies H60 as a major minor histocompatibility antigen in murine graft-versus-host disease.

Although CD8 T cells are thought to be a principal effector population of graft-versus-host disease (GVHD), their dynamics and specificity remain a mystery. Using a mouse model in which donor and recipient were incompatible at many minor histocompatibility antigens (minor H Ags), the CD8 T-cell response was tracked temporally and spatially through the course of GVHD. Donor CD8 T cells in the circulation, spleen, lung, and liver demonstrated virtually identical kinetics: rapid expansion and then decline prior to morbidity. Remarkably, up to one fourth of the CD8 T cells were directed against a single minor antigen, H60. Extreme H60 immunodominance occurred regardless of sampling time, site, and genetic background. This study is the first to analyze the T cells participating in GVHD in "real-time," demonstrates the exceptional degree to which immunodominance of H60 can occur, and suggests that such superdominant minor H Ags could be risk factors for GVHD.

Animals↗

PubMed2002

Cutting edge: the minor histocompatibility antigen H60 peptide interacts with both H-2Kb and NKG2D.

Minor histocompatibility Ags elicit cell-mediated immune responses and graft rejection in individuals receiving MHC-matched tissues. H60 represents a dominant Ag that elicits a strong CTL response in C57BL/6 mice immunized against BALB.B. An 8-aa peptide in the H60 protein is presented by H-2K(b) and this is recognized by the TCR as an alloantigen. The intact H60 glycoprotein is a ligand for the costimulatory NKG2D receptor that is expressed by activated CD8(+) T cells. Thus, H60 may provide both an allogeneic peptide and its own costimulation. We show that mutation of an H-2K(b)-binding anchor residue in the H60 peptide completely abrogates binding of H60 glycoprotein to NKG2D and a synthetic H60 peptide partially blocks the binding of NKG2D to its ligand. Ligands of the human NKG2D receptor are remarkably polymorphic, suggesting that these may also serve as minor histocompatibility Ags.

Animals↗

PubMed2002

Immunodominance of H60 is caused by an abnormally high precursor T cell pool directed against its unique minor histocompatibility antigen peptide.

The H60 minor histocompatibility (H) antigen peptide is derived from a glycoprotein that serves as a ligand for the stimulatory NKG2D receptor. We show that this peptide is remarkably immunodominant in that it competes effectively with MHC alloantigens, is efficiently crosspresented by host antigen-presenting cells (APCs), and readily elicits naive CD8 T cell responses in vitro. H60 immunodominance is neither a consequence of NKG2D engagement nor competition among minor H antigens on APCs. Instead, H60 immunodominance is a consequence of an abnormally high naive precursor frequency of H60 peptide reactive CD8 T cells. Understanding why the H60 peptide is so immunogenic has important implications in tissue transplantation and vaccine design.

Animals↗

PubMed2002

Genetic susceptibility to chronic periodontal disease.

Evidence suggests that there is a significant genetic component to susceptibility and resistance to chronic periodontal disease. Data from both clinical studies and studies using animal models are reviewed here. Also outlined are the genomic methods that are now available for identifying susceptibility and resistance loci.

Animals↗