STUDIES ON THE CLASS I GLYCOPROTEINS OF THE MURINE MAJOR HISTOCOMPATIBILITY COMPLEX (TRANSPLANTATION ANTIGEN, LYMPHOCYTE, CELL SURFACE MOLECULE)

A series of studies were undertaken to analyze and compare various aspects of murine class I glycoproteins. An initial area of investigation characterized the Qa-1 alloantigens using two-dimensional gel electrophoresis. Analysis of the products of the Qa-1('b), Qa-1('c) and Qa-1('d) alleles indicated that these were distinct molecules as determined by their lack of comigration upon comparative two-dimensional gel analysis. The importance of asparagine-linked glycosylation in the cell surface expression of class I molecules was also examined. These studies employed tunicamycin, an inhibitor of N-linked glycosylation. Tunicamycin treatment of activated T lymphocytes diminished the surface expression of Qa-1 to undetectable levels; the levels of other class I molecules exhibited little or no decrease. These results indicated that N-linked glycosylation has a differential importance in the cell surface expression of various class I molecules. The molecular weight diversity of class I molecules was also investigated. Molecular weight determination of both the fully glycosylated and unglycosylated forms of H-2 and Qa/Tla region encoded molecules established that there is a significant variation in the sizes of these forms of various class I molecules. The most significant difference ((TURN)9,000 daltons) exists between the unglycosylated forms of H-2K('b) and Qa-2, suggesting that the structural organization of these two molecules may be very different. A comparative two-dimensional gel analysis of various class I glycoproteins isolated from resting and activated T and B lymphocytes indicated that class I molecules expressed on activated T cells exhibited an isoelectrophoretic pattern that was distinct from the isoelectrophoretic pattern of class I molecules expessed on the other cell populations. This difference was attributed to a lower sialic acid content of the molecules expressed on activated T cells. Analysis of cell homogenates determined that activated T cells contained a higher level of endogenous neuraminidase activity than was detected in the other populations, suggesting that this may be the basis of the lower sialic acid content. The relationship of the Qa-4 and Qa-2 alloantigens was also examined. It was established that upon mitogen activation, the expression of Qa-4 was greatly decreased, whereas Qa-2 expression was not decreased. However, an anti-Qa-2 monoclonal antibody blocked the binding of an anti-Qa-4 monoclonal antibody to resting cells. These studies established that Qa-4 is a determinant restricted to resting cells, which is closely associated on the surface with the Qa-2 molecule. ^

Immune responses against major histocompatibility complex and interleukin-2 gene transfected K1735 murine melanoma: Potential vaccines for the immunotherapy of cancer

Tumor specific immunity is mediated by cytotoxic T lymphocytes (CTL) that recognize peptide antigen (Ag) in the context of major histocompatibility complex (MHC) class I molecules and by helper T (Th) lymphocytes that recognize peptide Ag in the context of MHC class II molecules. The purpose of this study is (1) to induce or augment the immunogenicity of nonimmunogenic or weakly immunogenic tumors by genetic modification of tumor cells, and (2) to use these genetically altered cells in cancer immunotherapy. To study this, I transfected a highly tumorigenic murine melanoma cell line (K1735) that did not express constitutively either MHC class I or II molecules with syngeneic cloned MHC class I and/or class II genes, and then determined the tumorigenicity of transfected cells in normal C3H mice. K1735 transfectants expressing either $\rm K\sp{k}$ or $\rm A\sp{k}$ molecules alone produced tumors in normal C3H mice, whereas most transfectants that expressed both molecules were rejected in normal C3H mice but produced tumors in nude mice. The rejection of K1735 transfectants expressing $\rm K\sp{k}$ and $\rm A\sp{k}$ Ag in normal C3H mice required both $\rm CD4\sp+$ and $\rm CD8\sp+$ T cells. Interestingly, the $\rm A\sp{k}$ requirement can be substituted by IL-2 because transfection of $\rm K\sp{k}$-positive/A$\sp{\rm k}$-negative K1735 cells with the IL-2 gene also resulted in abrogation of tumorigenicity in normal C3H mice but not in nude mice. In addition, 1735 $(\rm I\sp+II\sp+)$ transfected cells can function as antigen presenting cells (APC) since they could process and present native hen egg lysozyme (HEL) to HEL specific T cell hybridomas. Furthermore, the transplantation immunity induced by K1735 transfectants expressing both $\rm K\sp{k}$ and $\rm A\sp{k}$ molecules completely cross-protected mice against challenge with $\rm K\sp{k}$-positive transfectants but weakly protected them against challenge with parental K1735 cells or $\rm A\sp{k}$-positive transfectants. Finally, I demonstrated that MHC $(\rm I\sp+II\sp+)$ or $\rm K\sp{k}$-positive/IL-2-positive cells can function as anti-cancer vaccines since they can abrogate the growth of established tumors and metastasis.^ In summary, my results indicate that expression of either MHC class I or II molecule alone is insufficient to cause the rejection of K1735 melanoma in syngeneic hosts and that both molecules are necessary. In addition, my data suggest that the failure of $\rm K\sp{k}$-positive K1735 cells to induce a primary tumor-rejection response in normal C3H mice may be due to their inability to induce the helper arm of the anti-tumor immune response. Finally, the ability of MHC $(\rm I\sp+II\sp+)$ or $\rm K\sp{k}$-positive/IL-2-positive cells to prevent growth of established tumors or metastasis suggests that these cell lines can serve as potential vaccines for the immunotherapy of cancer. (Abstract shortened by UMI.) ^

The genetic contribution of the major histocompatibility complex to bleomycin-induced lung injury

Pulmonary fibrosis (PF) is the result of a variety of environmental and cancer treatment related insults and is characterized by excessive deposition of collagen. Gas exchange in the alveoli is impaired as the normal lung becomes dense and collapsed leading to a loss of lung volume. It is now accepted that lung injury and fibrosis are in part genetically regulated. ^ Bleomycin is a chemotherapeutic agent used for testicular cancer and lymphomas that induces significant pulmonary toxicity. We delivered bleomycin to mice subcutaneously via a miniosmotic pump in order to elicit lung injury (LI) and quantified the %LI morphometrically using video imaging software. We previously identified a quantitative trait loci, Blmpf-1(LOD=17.4), in the Major Histocompatibility Complex (MHC), but the exact genetic components involved have remained unknown. ^ In the current studies, Blmpf-1 was narrowed to an interval spanning 31.9-32.9Mb on Chromosome 17 using MHC Congenic mice. This region includes the MHC Class II and III genes, and is flanked by the TNF-alpha super locus and MHC Class I genes. Knockout mice of MHC Class I genes (B2mko), MHC Class II genes (Cl2ko), and TNF-alpha (TNF-/-) and its receptors (p55-/-, p75-/-, and p55/p75-/-) were treated with bleomycin in order to ascertain the role of these genes in the pathogenesis of lung injury. ^ Cl2ko mice had significantly better survival and %LI when compared to treated background BL/6 (B6, P<.05). In contrast, B2mko showed no differences in survival or %LI compared to B6. This suggests that the MHC Class II locus contains susceptibility genes for bleomycin-induced lung injury. ^ TNF-alpha, a Class III gene, was examined and it was found that TNF-/- and p55-/- mice had higher %LI and lower survival when compared to B6 (P<.05). In contrast, p75-/- mice had significantly reduced %LI when compared to TNF-/-, p55-/-, and B6 mice as well as higher survival (P<.01). These data contradict the current paradigm that TNF-alpha is a profibrotic mediator of lung injury and suggest a novel and distinct role for the p55 and p75 receptors in mediating lung injury. ^

Mapping T-cell epitopes of the rubella virus structural proteins

Rubella virus (RV) typically causes a mild childhood illness, but complications can result from both viral and immune-mediated pathogenesis. RV can persist in the presence of neutralizing antibodies, suggesting that cell-mediated immune responses may be necessary for viral clearance. However, the molecular determinants recognized by RV-specific T-cells have not been identified. Using recombinant proteins which express the entire RV structural open reading frame in proliferation assays with lymphocytes of RV-immune individuals, domains which elicit major histocompatibility complex class II-restricted helper T-cells were identified. Synthetic peptides representing these domains were used to define specific epitopes. Two immunodominant domains were mapped to the capsid protein sequence C$\sb1$-C$\sb{29}$ and the E1 glycoprotein sequence E1$\sb{202}$-E1$\sb{283}.$ RV-specific MHC class I-restricted cytotoxic T lymphocytes (CTLs) were identified using a chromium-release assay with infected fibroblasts as target cells. An infectious Sindbis virus vector expressing each of the RV structural proteins identified the capsid, E2 and E1 proteins as targets of CTLs. Specific CTL epitopes were mapped within the previously identified immunodominant domains. This study identified domains of the RV structural proteins that may be beneficial for development of a synthetic vaccine, and provides normative data on RV-specific T-cell responses that should enhance our ability to understand RV persistence and associated complications. ^

Transcriptional regulation of the invariant chain associated with MHC class II molecules

The invariant chain associated with the major histocompatibility complex (MHC) class II molecules is a non-polymorphic glycoprotein implicated in antigen processing and class II molecule intracellular transport. Class II molecules and invariant chain (In) are expressed primarily by B lymphocytes and antigen-presenting cells such as macrophages and can be induced by interferon gamma (IFN-$\gamma$) in a variety of cell types such as endothelial cells, fibroblasts, and astrocytes. In this study the cis-acting sequences involved in the constitutive, tissue-specific, and IFN-$\gamma$ induced expression of the human In gene were investigated and nuclear proteins which specifically bound these sequences were identified.^ To define promoter sequences involved in the regulation of the human In gene, 790 bp 5$\sp\prime$ to the initiation of transcription were subcloned upstream of the gene encoding chloramphenicol acetyl transferase (CAT). Transfection of this construct into In expressing and non-expressing cell lines demonstrated that this 790 bp In promoter sequence conferred tissue specificity to the CAT gene. Deletion mutants were created in the promoter to identify sequences important for transcription. Three regulatory regions were identified $-$396 to $-$241, $-$241 to $-$216, and $-$216 to $-$165 bp 5$\sp\prime$ to the cap site. Transfection into a human glioblastoma cell line, U-373 MG, and treatment with IFN-$\gamma$, demonstrated that this 5$\sp\prime$ region is responsive to IFN-$\gamma$. An IFN-$\gamma$ response element was sublocalized to the region $-$120 to $-$61 bp. This region contains homology to the interferon-stimulated response element (ISRE) identified in other IFN responsive genes. IFN-$\gamma$ induces a sequence-specific DNA binding factor which binds to an oligonucleotide corresponding to $-$107 to $-$79 bp of the In promoter. This factor also binds to an oligonucleotide corresponding to $-$91 to $-$62 of the interferon-$\beta$ gene promoter, suggesting this factor may be member of the IRF-1/ISGF2, IRF-2, ICSBP family of ISRE binding proteins. A transcriptional enhancer was identified in the first intron of the In gene. This element, located in a 2.6 kb BamHI/PstI fragment, enhances the IFN-$\gamma$ response of the promoter in U-373 MG. The majority of the In enhancer activity was sublocalized to a 550 bp region $\sim$1.6 kb downstream of the In transcriptional start site. ^

Deviation of the alloimmune response toward tolerance by chimeric class I MHC molecules

Class I major histocompatibility complex (MHC) molecules induce either accelerated rejection or prolonged survival of allografts, presumably because of the presence of immunogenic or tolerogenic epitopes, respectively. To explore the molecular basis of this phenomenon, three chimeric class I molecules were constructed by substituting the rat class I RT1.A$\sp{\rm a}$ sequences with the N-terminus of HLA-A2.1 (N$\sp{\rm HLA-A2.1}$-RT1.A$\sp{\rm a}$), the $\alpha\sb1$ helix (h) with $\rm\alpha\sb{1h}\sp{u}$ sequences ( ($\rm\alpha\sb{1h}\sp{u}$) -RT1.A$\sp{\rm a}$) or the entire $\alpha\sb2$ domain (d) with $\rm\alpha\sb{2d}\sp{u}$ sequences ( ($\rm\alpha\sb{2d}\sp{u}$) -RT1.A$\sp{\rm a}$). Wild type (WT) and chimeric cDNAs were sequenced prior to transfection into Buffalo (BUF; RT1$\sp{\rm b}$) hepatoma cells. Stable transfectants were injected subcutaneously (s.c.) into different hosts 7 days prior to challenge with a heart allograft. In BUF hosts, chimeric ($\rm\alpha\sb{1h}\sp{u}$) -RT1.A$\sp{\rm a}$ accelerated the rejection of Wistar Furth (WF; RT1$\sp{\rm u}$) heart allografts, but had no effect on the survival of ACI (RT1$\sp{\rm a}$) grafts. In contrast, the ($\rm\alpha\sb{2d}\sp{u}$) -RT1.A$\sp{\rm a}$ (containing $\rm\alpha\sb{1d}\sp{a}$ sequences) immunized BUF recipients toward RT1$\sp{\rm a}$ grafts. In WF hosts, WT-RT1.A$\sp{\rm a}$ was a potent immunogen and accelerated ACI graft rejection, N$\sp{\rm HLA-A2.1}$-RT1.A$\sp{\rm a}$ was less effective and ($\rm\alpha\sb{\rm 1h}\sp{u}\rbrack$-RT1.A$\sp{\rm a}$ was not immunogenic. Thus, dominant and subdominant epitopes inducing in vivo sensitization to cardiac allografts are present in the $\alpha\sb1$ helix and the N-terminus, respectively. The failure of ($\rm\alpha\sb{2d}\sp{u}$) -RT1.A$\sp{\rm a}$ transfectants (containing recipient-type $\alpha\sb{\rm 2d}$ sequences) to sensitize WF hosts toward ACI (RT1$\sp{\rm a}$) grafts, despite the presence of donor-type immunogenic $\alpha\sb{\rm 1d}\sp{\rm a}$, suggests that "self-$\alpha\sb2$" sequences displayed on chimeric antigens interfere with immunogenicity. The ($\rm\alpha\sb{1h}\sp{u}$) -RT1.A$\sp{\rm a}$ transfectants injected s.c. prolonged the survival of WF (RT1$\sp{\rm u}$) hearts in ACI (RT1$\sp{\rm a}$) recipients. Furthermore, intra-portal injection of extracts from ($\rm\alpha\sb{1h}\sp{u}$) -RT1.A$\sp{\rm a}$, but not WT-RT1.A$\sp{\rm a}$ or RT1.A$\sp{\rm u}$, in conjunction with a brief cyclosporine course rendered ACI hosts permanently and specifically tolerant to donor-type WF cardiac allografts. Thus, immunodominant allodeterminants are present in the $\alpha\sb1$, but not the $\alpha\sb2$, domain of rat class I MHC molecules. Furthermore, the $\rm\alpha\sb{1h}\sp{u}$ immunogenic epitopes trigger tolerogenic responses when flanked by host-type N-terminal$\sp{\rm a}$ and $\rm\alpha\sb{2d}\sp{a}$ sequences. ^

AUTOIMMUNE RESPONSES TO ATHEROSCLEROTIC

Atherosclerosis is a chronic, complex arterial disease characterized by intimal lipid accumulation and inflammation. A unique lipid-binding molecule, namely cluster of differentiation 1d (CD1d), may impact atherosclerosis. Structurally, CD1d acts as a nonpolymorphic cell-surface receptor, resembling the major histocompatibility complex-I (MHC-I). While MHC-I restricts peptide antigen presentation to T cells, CD1d presents lipid antigens to T cells named CD1d-restrictedd T cells. Although increased expression of CD1d has been found in human plaques, the exact nature of CD1d-recognized lipids in atherosclerosis remains to be determined. Three groups of lipids may undergo oxidation in atherosclerosis producing atherogenic lipids: phospholipids, fatty acids, and cholesterol. The central hypothesis is that CD1d recognizes and present oxidative lipids to activate CD1d-restricted T cells, and trigger proinflammatory signal transduction In the first part of this study, oxidative phospholipids were identified and characterized as potential autoantigen for CD1d-restricted T cells. Derived from phospholipid 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine by oxidization, 1-palmitoyl-2-glutaryl-sn-glycero-3-phosphocholine (PGPC) is commonly found in atherosclerotic plaques. Upon stimulation with PGPC, spleen-derived CD1d-restricted T cells produced higher levels of cytokines and proliferated at higher rates than those without PGPC stimulation. CD1d deficiency compromised the PGPC-triggered T cell activation, suggesting that PGPC may function as a potentially novel autoantigen for T cells in atherosclerosis. In the second part of this study, CD1d-mediated proinflammatory signaling was evaluated in murine models. Enhanced CD1 expression occurred in spleens of db/db mice with hyperlipidemia. Tumor necrosis factor-alpha (TNF-α) was increased in db/db spleen, while TNF-α receptor expression augmented in the db/db murine heart, in comparison with those in normal mice. The nuclear factor-κ B (NF-κB) expression was enhanced in the db/db heart, whereas CD1d-null mice showed lower NF-κB, implying the involvement of CD1d in inflammation of the spleen and heart tissues in the mice with hyperlipidemia. The current study has identified PGPC as a novel lipid antigen recognized by CD1d-restricted T cells in atherosclerosis. The animal study has also provided evidence that CD1d regulates NF-κB-mediated proinflammatory signaling. Hence, CD1d-restricted T cell responses to autolipid antigen and mediated inflammatory signal may represent a new molecular pathway that triggers cardiovascular tissue injury in atherosclerosis and hyperlipidemia.

Generation and characterization of antigenic variants induced by exposure of tumor cells to UV radiation in vitro

Antigenic changes present in nonantigenic tumor cells exposed to UV radiation (UV) in vitro were investigated by addressing the following questions: (1) Are antigenic variants (AV) produced that are rejected in normal but not immunosuppressed mice? (2) Does generation of AV depend upon intrinsic properties of the cells exposed or result from the action of UV? (3) Is antigenic modification induced by UV due to increased histocompatibility antigen expression? (4) Do AV crossreact immunologically with parental tumor or with other AV? and (5) Is the UV-associated common antigen expressed on UV-induced tumors present on UV-irradiated tumor cells? AV were generated at different frequencies following in vitro UV irradiation of a spontaneous murine fibrosarcoma (51% of cell lines tested), a murine melanoma (56%), and two melanoma clones (100% and 11%). This indicated that the percentage of AV produced is an intrinsic property of the cell line exposed. The increased antigenicity did not correlate with an increased expression of class I histocompatibility antigens. Immunological experiments demonstrated that the AV and parental cells shared a determinant that was susceptible to immune recognition, but incapable of inducing immunity. In contrast, the AV were noncrossreactive, suggesting that variant-specific antigens were also expressed. Finally, the AV were recognized by UV-induced suppressor cells, indicating that the UV-associated common antigen expressed by UV-induced tumors was also present. This investigation provides new information on the susceptibility of tumors to antigenic modification by UV and on the relationship between tumor antigens and neoplastic transformation. Furthermore, it suggests an immunological approach for cancer therapy. ^

ANTIBODY-DEPENDENT AND ANTIBODY-INDEPENDENT CELLULAR CYTOTOXICITY AGAINST SHIGELLA

Diarrhea is a major cause of morbidity and mortality worldwide. Shigella causes up to 20% of all diarrhea. Gut-level immunity and breast-feeding of infants are important factors in protection against shigellosis. The lumen of the gut is lined with lymphocytes which mediate natural killer cytotoxicity, NKC, and antibody-dependent cellular cytotoxicity, ADCC. NKC and ADCC are extracellular, nonphagocytic leukocyte killing mechanisms, which occur in the absence of complement, without prior antigen stimulation, and without regard to the major histocompatibility complex. In this study, virulent and avirulent shigellae were used as the target cells. Leukocytes from peripheral blood, breast milk, and guinea pig gut-associated tissues were used as effector cells. Adult human peripheral blood mononuclear cells and lymphocytes, but not macrophages or polymorphonuclear leukocytes, mediated NKC and ADCC at an optimal effector to target cell ratio of 100:1 in a 60 minute bactericidal assay. An antiserum dilution of 1:10 was optimal for ADCC. Whole, viable lymphocytes were necessary for cytotoxicity. Lymphocyte NKC, but not ADCC, was greatly enhanced by interferon. Lymphocyte NKC occurred against several virulent strains of S. sonnei and a virulent strain of S. flexneri. ADCC (using immune serum directed against S. sonnei) occurred against virulent S. sonnei, but not against avirulent S. sonnei or virulent S. flexneri. Lymphocyte ADCC was not inhibited by the presence of phenylbutazone or by pretreatment of lymphocytes with anti-HNK serum plus complement. Both adherent and non-adherent breast milk leukocytes mediated NKC and ADCC. Mononuclear cells from young children demonstrated normal ADCC, when compared to ADCC of adult cells. Neonatal cord blood and a CGD patient's peripheral blood mononuclear and ploymorphonuclear cells demonstrated high ADCC compared to adult cells. Intraepithelial lymphocytes, spleen cells, and peritoneal cells from normal guinea pigs demonstrated NKC and ADCC. Animals which had been starved and opiated were made susceptible to infection by Shigella. The susceptible animals demonstrated deficient NKC and ADCC with all three leukocyte populations. High NKC and ADCC activity of gut-associated leukocytes from human breast milk and guinea pig tissues may correlate with resistance to infection. ^

B cell memory and idiotype network regulation

This investigation examined the clonal dynamics of B-cell expression and evaluated the role of idiotype network interactions in shaping the expressed secondary B-cell repertoire. Three interrelated experimental approaches were applied. The first approach was designed to distinguish between regulatory influences controlled by the major histocompatibility complex (MHC) and regulatory influences controlled by non-MHC factors including the idiotype network. This approach consisted of studies on the clonal dynamics and heterogeneity of the expressed IgG antibody repertoire of BALB/c mice. The second approach involved the analysis of the clonal dynamics of antibody responses of outbred rabbits. This analysis was coupled with studies to detect the occurrence and activity of constituents of the idiotype network. In the third approach the transfer of rabbit lymphocytes from immunized donors to MHC matched naive recipients was used to examine the effects of recipient non-MHC immunoregulatory influences on the expression of donor memory B-cells. Although many memory B cells were unaffected by non-MHC influences, these data show that non-MHC immunoregulatory influences can affect the expression of B-cells in the secondary response of inbred mice and outbred rabbits. The results also indicate that most IgG antibody responses are heterogeneous and are characterized by a stable group of dominant clonotypes. Clonal dominance and B-cell memory were found to be established early in an immune response. The expression of B memory clones appeared to be favored over the expression of virgin B cells. The injection of anti-tetanus antibody induced the antigen independent production of anti-tetanus antibody, probably through idiotypic mechanisms. These results demonstrate that both antibody and antigen can affect the expressed B-ceIl repertoire. Thus, idiotypic interactions are capable of influencing the expression of B-cells and these findings support the existence and function of an idiotype network with strong immunoregulatory potential. ^

Tumor immunization strategies for enhancing the graft versus tumor activity of allogeneic bone marrow transplantation

Allogeneic bone marrow transplantation (BMT) is known to induce a beneficial anti-tumor immune response called graft-versus-tumor (GVT) activity. However, GVT activity is closely associated with graft-versus-host disease (GVHD), a potentially fatal immune response against antigens on normal recipient tissues. The T-cell populations mediating these two processes are often overlapping, but studies have shown that some donor T-cells can be tumor-specific. Therefore, the goal of this study was to develop strategies for preferentially activating donor T-cells capable of mediating GVT activity but not GVHD. The three hypotheses tested were: (1) Pre-transplant immunization of BMT donors with a recipient-derived tumor cell vaccine will induce a relative increase in GVT activity as compared to GVHD. (2) Post-transplant tumor immunization of BMT recipients will enhance GVT activity without exacerbating GVHD. (3) Pre-transplant immunization of BMT donors against a tumor-specific antigen will enhance GVT activity without exacerbating GVHD. ^ To test the first two hypotheses, C3H.SW mice (MHC-matched donors) were immunized with a C57BL/6 (recipient)-derived tumor cell vaccine (leukemia or fibrosarcoma) prior to BMT, or recipients were immunized starting one month after BMT. Both donor and recipient immunization led to a significant increase in GVT activity (enhanced recipient survival and decreased tumor growth). However, donor immunization also increased fatal GVHD, which was at least partially due to activation of alloreactive T-cells recognizing the immunodominant minor histocompatibility antigen B6dom1. GVT immunity following recipient immunization was not associated with an exacerbation of GVHD or a response to B6dom1. ^ To test the third hypothesis, influenza nucleoprotein (NP) was used as a model tumor antigen. C3H.SW donors were immunized against NP prior to BMT, which led to a significant increase in GVT activity. Although recipients were not completely protected against growth of antigen loss variant tumors, there was no increase in GVHD. ^ In conclusion, (1) immunization of allogeneic BMT donors with a recipient-derived tumor cell vaccine substantially increases GVT activity but also exacerbates GVHD, (2) post-transplant tumor immunization of allogeneic BMT recipients significantly increases GVT activity and survival without exacerbating GVHD, and (3) immunization of allogeneic BMT donors against a tumor-specific antigen significantly enhances GVT activity without exacerbating GVHD. ^

Congenital diaphragmatic hernia in the preterm infant.

BACKGROUND: Congenital diaphragmatic hernia (CDH) remains a significant cause of death in newborns. With advances in neonatal critical care and ventilation strategies, survival in the term infant now exceeds 80% in some centers. Although prematurity is a significant risk factor for morbidity and mortality in most neonatal diseases, its associated risk with infants with CDH has been described poorly. We sought to determine the impact of prematurity on survival using data from the Congenital Diaphragmatic Hernia Registry (CDHR). METHODS: Prospectively collected data from live-born infants with CDH were analyzed from the CDHR from January 1995 to July 2009. Preterm infants were defined as <37 weeks estimated gestational age at birth. Univariate and multivariate logistic regression analysis were>performed. RESULTS: During the study period, 5,069 infants with CDH were entered in the registry. Of the 5,022 infants with gestational age data, there were 3,895 term infants (77.6%) and 1,127 preterm infants (22.4%). Overall survival was 68.7%. A higher percentage of term infants were treated with extracorporeal membrane oxygenation (ECMO) (33% term vs 25.6% preterm). Preterm infants had a greater percentage of chromosomal abnormalities (4% term vs 8.1% preterm) and major cardiac anomalies (6.1% term vs 11.8% preterm). Also, a significantly higher percentage of term infants had repair of the hernia (86.3% term vs 69.4% preterm). Survival for infants that underwent repair was high in both groups (84.6% term vs 77.2% preterm). Survival decreased with decreasing gestational age (73.1% term vs 53.5% preterm). The odds ratio (OR) for death among preterm infants adjusted for patch repair, ECMO, chromosomal abnormalities, and major cardiac anomalies was OR 1.68 (95% confidence interval [CI], 1.34-2.11). CONCLUSION: Although outcomes for preterm infants are clearly worse than in the term infant, more than 50% of preterm infants still survived. Preterm infants with CDH remain a high-risk group. Although ECMO may be of limited value in the extremely premature infant with CDH, most preterm infants that live to undergo repair will survive. Prematurity should not be an independent factor in the treatment strategies of infants with CDH.

RELATIONSHIP OF ANTISOCIAL PERSONALITY SYNDROME IN BOYS TO PARENTAL ALCOHOL/DRUG DEPENDENCY

The study focused on the relationship between antisocial personality syndrome in boys ages 8-15 and parental alcohol/drug dependency. The population studied was case records of 101 boys coming to a private psychiatrist from 1966 through 1979. The boys were predominantly white and from middle to upper income families.^ A boy was determined to have antisocial personality syndrome if he exhibited antisocial behaviors in four or five major categories, did not exhibit a brain syndrome, and did not exhibit a thought disorder. The five major behavior categories were: (1) self-control (i.e., temper tantrums or hyperactivity), (2) behavior at home (i.e., disobedience or lying), (3) behavior at school (i.e., truancy or cheating), (4) behavior toward peers (i.e., bullying, fighting, or tattling), and (5) behavior against property (i.e., destructiveness or stealing). A boy was determined to be a control if he exhibited antisocial behaviors in two or less behavior categories.^ A parent was determined to have alcohol/drug dependency if s/he exhibited a score above the established threshold (1) for the MacAndrew Alcoholism Scale (28 or above), and (2) for the Holmes Alcoholism Scale (35 or above) which are used with the MMPI. A parent was classified not alcohol/drug dependent if s/he had scores below set thresholds (22 on the MacAndrew Alcoholism Scale and 28 on the Holmes Alcoholism Scale).^ For the final sample (N = 10), there was no reason to believe a relationship exists between antisocial personality syndrome in boys ages 8-15 and parental alcohol/drug dependency (Fisher's Exact Test {FET} P = 1.0). The small sample size primarily occurred as a result of 88.12% of the parents being classified in a questionable category in terms of alcohol/drug dependency.^ The sample was suggestive of a relationship between the fathers' Psychopathic Deviate (Pd) Scale scores as a measure of antisocial tendencies and the boy having antisocial personality syndrome (N = 75; P = .12). There was no evidence of such a relationship for mothers (N = 75; P = .97). ^

Ethnic comparisons of adolescent sexual risk -taking and preventive behavior

For adolescents, unprotected sexual intercourse is the primary cause of sexually transmitted disease (STD), including Human Immunodeficiency Virus (HIV) infection (virus which causes Acquired Immunodeficiency Syndrome (AIDS)), and pregnancy. Although many studies on adolescent sexual behavior have addressed racial/ethnic differences, few studies have examined the relation between race/ethnicity while controlling for other sociocultural and psychosocial variables. The purpose of this study is to examine the relationship between racial/ethnic categories and selected sociocultural and psychosocial variables, with reported adolescent sexual risk-taking and preventive behavior.^ A self-administered questionnaire was used to collect information from 3132 students in a Texas school district (Section 3.5.2). The instrument contained approximately 100 questions on demographic characteristics, sexual behavior, and psychosocial determinants of sexual behavior. Based on the findings of this study, the following major conclusions are made: (1) There are differences in reported sexual risk-taking and preventive behavior among Black, Hispanic and White adolescents in this study. The stratified analysis by gender further suggests significant gender differences in reported sexual behavior among the three racial/ethnic groups. (2) Gender, living arrangement, academic grades, and language spoken at home modified the association between reported sexual risk-taking and preventive behavior and race/ethnicity in this study. This suggests that these sociocultural variables should be considered in future research and practice involving multicultural populations. (3) There are differences in selected psychosocial determinants among the three racial/ethnic groups and between males and females. These differences were consistent with the reported sexual risk-taking and preventive behaviors among race/ethnicity and gender for adolescents in this study. The findings support the consideration of psychosocial determinants in research and interventions addressing adolescent sexual behavior among different racial/ethnic groups.^ Based on the results of this study, two recommendations for practice are made. First, health professionals developing interventions for adolescents from different cultural backgrounds and gender need to be familiar with the specific sociocultural and psychosocial factors which will reduce risky sexual behavior, and promote protective behavior. Second, the need for immediate, realistic, and continuous HIV/STD and pregnancy prevention programs for children and adolescents should be considered. ^