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Biomedical subjects

M Fotino

Publications and source records attributed to M Fotino.

At least 19 recordsLinked to original sources
PubMed2000

Identification of HLA-A*03, A*11 and B*07-restricted melanoma-associated peptides that are immunogenic in vivo by vaccine-induced immune response (VIIR) analysis.

With the discovery of increasing numbers of tumor antigens, there is a need to rapidly determine whether these antigens and the individual peptides they express are able to stimulate immune responses in vivo and thus, can be used to construct cancer vaccines. In this study we used the method of vaccine-induced immune response (VIIR) analysis to identify multiple immunogenic peptide epitopes derived from several melanoma associated antigens and presented by HLA-A*03, A*11 and B*07. Thirty-one patients with melanoma were immunized to a polyvalent vaccine containing multiple antigens, including MAGE-3, Melan A/MART-1, gp100 and tyrosinase. Their peripheral blood was tested for peptide-specific, vaccine-induced CD8+ T cell responses before and after immunization using an enzyme-linked immune spot (ELISPOT) assay with panels of peptides restricted by these three alleles. The peptides were selected for immunogenic potential based on their strong binding affinity in vitro to HLA-A*03, A*11 or B*07. Overall, 60% of the 20 peptides studied were recognized by at least one patient and 50% of the patients showed a vaccine-induced CD8+ T cell response to at least one peptide that matched their HLA specificity. We conclude that VIIR analysis is an effective strategy to directly identify immunogenic peptides that are good candidates for vaccine construction.

Alleles↗
PubMed2000

Fine specificity of anti-fibrillin-1 autoantibodies in primary pulmonary hypertension syndrome.

Autoantibodies to fibrillin-1 (Fbn-1) have been found in systemic sclerosis (SSc), calcinosis, Raynaud's esophagael dysmotility, sclerodectyly, and telaengectasia (CREST) and mixed connective tissue disease (MCTD) diseases. The purpose of this study was to determine whether patients with primary pulmonary hypertension (PPH) and appetite-suppressant-associated PPH have anti-Fbn-1 autoantibodies. In addition we assessed the human leucocyte antigen (HLA) class II alleles (DRB1, 3, 4, 5 and DQB1) in these patients in order to determine whether the response is genetically restricted. The frequency of anti-Fbn-1 autoantibodies in patient groups was compared with that of a control group of 88 healthy patients, and HLA was correlated similarly with a group of 51 healthy subjects. Anti-Fbn-1 autoantibodies were found at high frequency in PPH: in 70 of 75 adults with PPH (93%), in 28 of 33 children with PPH (84.8) and in 12 of 18 (67%) patients with appetite-suppressant-associated PPH. Utilization of two Fbn-1 fusion proteins allowed us to determine the dominant determinant region, recognized by anti-Fbn-1 autoantibodies, which may be located on the N-terminal fragment of the Fbn-1 protein. No significant immunogenetic correlations were found when the PPH patient groups were compared with normal controls. This novel category of autoantibodies is found in diseases characterized by endothelial and extracellular matrix protein alterations and fibrosis.

Adult↗
PubMed1998

HLA-independent heterogeneity of CD8+ T cell responses to MAGE-3, Melan-A/MART-1, gp100, tyrosinase, MC1R, and TRP-2 in vaccine-treated melanoma patients.

An important element in melanoma vaccine construction is to identify peptides from melanoma-associated Ags that have immunogenic potential in humans and are recognized by CD8+ T cells in vivo. To identify such peptides, we evaluated HLA-A*02+ melanoma patients immunized to a polyvalent vaccine containing multiple Ags, including MAGE-3, Melan-A/MART-1, gp100, tyrosinase, melanocortin receptor (MC1R), and dopachrome tautomerase (TRP-2). Using a filter spot assay, we measured peripheral blood CD8+ T cell responses, before and after immunization, to a panel of 45 HLA-A*0201-restricted peptides derived from these Ags. The peptides were selected for immunogenic potential based on their strong binding affinity in vitro to HLA-A*0201. Vaccine treatment induced peptide-specific CD8+ T cell responses to 22 (47.8%) of the peptides. The most striking finding was the HLA-independent heterogeneity of responses to both peptides and Ags. All responding patients reacted to different combination of peptides and Ags even though the responding patients were all A*0201+ and the peptides were all A*0201-restricted. From 9 to 27% of patients developed a CD8+ T cell response to at least one peptide from each Ag, but no more than 3 (14%) reacted to the same peptide from the same Ag. This heterogeneity of responses to individual peptides and Ags in patients with the same haplotype points to the need to construct vaccines of multiple peptides or Ags to maximize the proportion of responding patients.

Alleles↗
PubMed1997

Stimulation of CD8+ T cell responses to MAGE-3 and Melan A/MART-1 by immunization to a polyvalent melanoma vaccine.

A critical requirement for cancer vaccines is that they stimulate CD8+ T cell responses. In this study, we tested the ability of a polyvalent melanoma vaccine to induce CD8+ T cell responses to the melanoma associated antigens MAGE-3 and Melan A/MART-1. Fifteen HLA-A2+ patients with resected malignant melanoma were immunized with the vaccine s.c. every 2-3 weeks. CD8+ T cells in peripheral blood reacting to HLA-A2 restricted epitopes on MAGE-3 (FLWGPRALV) and Melan A/MART-1/(AAGIGILTV) were quantitated using a filter spot assay at baseline and following 4 immunizations. Vaccine immunization induced CD8+ T cells reacting to one or both of these peptides in 9 of the 15 (60%) patients. These cells were CD8+ and HLA-A2 restricted, as reactivity was abrogated by monoclonal antibodies (MAbs) to CD8 and class I HLA, but not by anti-CD4. All responding patients remained recurrence-free for at least 12 months (median 15 months, range 12 to >21 months), whereas melanoma recurred within 3-5 months in non-responders. The differences in outcome were unrelated to differences in disease severity or overall immunological competence between responders and non-responders. Our results demonstrate directly that MAGE-3 and Melan A/MART-1 can stimulate CD8+ T cell responses in humans, and suggest that these responses are protective and surrogate markers of vaccine efficacy.

Amino Acid Sequence↗
PubMed1997

Primary pulmonary hypertension, tissue plasminogen activator antibodies, and HLA-DQ7.

Antibodies to fibrin-bound tissue plasminogen activator (tPA) have been found in autoimmune diseases with vascular injury, such as systemic lupus erythematosus and scleroderma. The purpose of this study was to determine whether patients with primary pulmonary hypertension (PPH) have an immunogenetically determined response to fibrin-bound tPA. Antibodies to fibrin-bound tPA were determined in three patient groups: 45 adults with PPH, 41 children with PPH, and 40 children with anatomically large congenital pulmonary to systemic communications (PHT+shunt). The frequencies of the HLA class II (DRB1,3,4,5, and -DQB1) alleles in these three patient groups were compared with those of 51 healthy Caucasian control subjects. Fibrin-bound tPA antibodies were found in four of 45 (9%) adults with PPH, four of 41 (10%) children with PPH, and one of 40 (2.5%) children with PHT-shunt. HLA class II typing, which was available for seven of nine Caucasians with fibrin-bound tPA antibodies, revealed that six of seven (86%) patients typed HLA-DQ7 (DQB1*0301) and one typed HLA-DQ6. The 86% frequency of HLA-DQ7 in the antibody positive patients was significant compared with the 29% frequency in the healthy control subjects (p = 0.007, p corrected [pc] = 0.05, OR = 14.4). Of interest, these antibody-positive patients, although lacking antiphospholipid antibodies, shared an amino acid epitope, common to HLA-DQB1*06,07 and 08 subtypes, which was previously reported to be associated with the lupus anticoagulant. In conclusion, antibodies to fibrin-bound tPA and HLA-DQ7, and possibly the same epitope associated with the lupus anticoagulant, defined a small subset of children and adults with PPH.

Adolescent↗
PubMed1996

Primary pulmonary hypertension: immunogenetic response to high-mobility group (HMG) proteins and histone.

HLA class II alleles (DNA typing) and antibodies to HMG-1,2,14,17 proteins and H1 histone were determined in three predominantly Caucasian groups of patients with pulmonary hypertension (PHT). Forty-four adults had primary pulmonary hypertension (PPH), 42 children had PPH, and 41 children had PHT associated with anatomically large congenital pulmonary to systemic shunts (PHT + shunt). The HLA class II alleles in the Caucasian patients were compared with those of 51 healthy Caucasian controls. Eight (18%) of 44 sera from adults with PPH bound HMG-14 and 23 (52%) bound H1. None of 42 sera from children with PPH bound either HMG-14/17 or HMG-1/2, whereas four (10%) bound H1. In the PHT + shunt group of 41 children, two (5%) bound HMG-14, one (3%) bound HMG-17, four (10%) bound HMG-1 and/or HMG-2, and six (15%) bound H1. Among the 12 HMG antibody-positive patients, HLA-DQ6 was present in nine of 10 HLA typed patients (six PPH adults and three PHT + shunt children), seven of whom had antibodies to HMG-14 and one to HMG-17. The 100% frequency of HLA-DQ6 in seven Caucasian patients with antibodies to HMG-14/17 was statistically significant when compared with the 41% frequency of -DQ6 present in 51 healthy Caucasian controls (pc = 0.027, pc = Bonferroni correction, OR = 21.3). In contrast, when compared with controls, 25 patients with PPH and anti-H1 antibodies (21 adults and four children) had increased frequencies of HLA-DQ7 and -DR5 (60% versus 29%, P = 0.010, OR = 3.6 and 48% versus 22%, P = 0.018, OR = 3.4), which were not significant after correction. In essence, antibodies to HMG-14 and to H1 proteins were present predominantly in adults with PPH, suggesting that the pattern of response to HMG-14/17 was similar to that previously reported in systemic lupus erythematosus (SLE) and drug-induced autoimmunity. This is the first report of an association between autoantibodies directed against HMG and H1 with immunogenetic markers. These data suggest that a subset of patients with PPH may have an autoimmune disease.

Adolescent↗
PubMed1996

Primary pulmonary hypertension in HIV infection: an outcome determined by particular HLA class II alleles.

Primary pulmonary hypertension (PPH) may have an autoimmune basis that is influenced by host immunogenetics. The pathogenesis of primary pulmonary hypertension in human immunodeficiency virus (HIV) infection is unclear. The objective of this study was to determine whether patients with PPH and HIV infection have distinctive immunogenetic profiles. Ten racially mixed HIV-infected patients with PPH were typed for human leukocyte antigen (HLA) class II (DRB1, 3, 4, 5 and DQB1) by DNA-PCR sequence-specific oligonucleotide probes. Results were compared with two control groups: 128 HIV-negative Caucasians and a previously reported group of 97 HIV-positive, racially mixed control subjects. In those with PPH, there was a significantly increased frequency of HLA-DR6 (-DRB1*1301/2 subtypes) and of HLA-DR52 (DRB3*0301 subtype). These findings suggest that HIV-associated PPH reflects a host response to HIV-1 determined by one or more HLA-DR alleles located within the major histocompatibility complex. The same HLA-DR6 subtype found at increased frequency in our patients has previously been associated with the development of a CD8 lymphocytic host response to HIV-1, termed diffuse infiltrative lymphocytosis syndrome (DILS), which resembles autoimmune Sjogren's disease and is associated with prolonged survival. Together, these findings suggest that HIV-positive PPH may represent a clinical outcome that has similarities with that resulting from the immunogenetically determined host response present in DILS.

Adult↗
PubMed1995

Position 26 of the first domain of the HLA-DQB1 allele in post-silicone implant scleroderma.

OBJECTIVE: To determine whether women with scleroderma (systemic sclerosis, SSc) and silicone implants have the same or distinctive immunogenetic findings compared to those reported for idiopathic scleroderma. METHODS: In this case-control study, 9 Caucasian women with SSc and silicone implants (7 breast, 1 chin, 1 toe) and 128 healthy Caucasian controls were typed for HLA class II (DRB1,3,4,5, and DQB1) by DNA polymerase chain reaction (PCR) sequence specific oligonucleotide probes (SSOP). RESULTS: All women with SSc had HLA-DQ5 or DQ7 (DQB1*0301). These 2 alleles have glycine (Gly) or tyrosine (Tyr), and not hydrophobic leucine (Leu), at position 26 in the 2nd hypervariable region of the DQB1 first domain. The increased frequency of at least one Leu 26 negative allele (Gly + or Tyr +) in the women with SSc (100%) compared with controls (73%) was not statistically significant. In contrast, the low frequency of one Leu 26+ allele in the patients (28 vs 57%, p = 0.03, RR = -3.3) and 2 Leu 26+ alleles (0 vs 35%, p = 0.03, RR = -10.4) was significant. CONCLUSION: The presence of Gly 26 or Tyr 26 in the HLA-DQB1 first domain in our cases with SSc and silicone implants is consistent with immunogenetic findings reported in Caucasian with idiopathic SSc anticentromere autoantibodies. Whether all the immunogenetic features in SSc associated with silicone implants remain indistinguishable from those seen in idiopathic.

Alleles↗
PubMed1993

Excellent outcome with a calcium channel blocker-supplemented immunosuppressive regimen in cadaveric renal transplantation. A potential strategy to avoid antibody induction protocols.

Many transplant centers routinely utilize monoclonal antibody or polyclonal antibody based induction protocols in recipients of cadaver renal allografts. Given the potential complications associated with antibody-based immunosuppression regimens (e.g., CMV disease), we tested the hypothesis that a combination of a calcium antagonist and a triple drug protocol (cyclosporine + prednisone + azathioprine) would be an effective substitute for antibody-based induction protocols in ensuring excellent patient and graft survival rates. Our postulate was tested in a prospective study of 52 consecutive recipients of cadaver renal allografts (44 first, 5 second, and 3 third grafts) utilizing nifedipine as the first line calcium antagonist. Nifedipine was selected over verapamil or diltiazem due to its lack of interference with the metabolism of CsA. Some of the significant outcomes of our prospective trial were (A) a cumulative patient survival rate of 98.1% for the 52 recipients at 18 months posttransplantation; (B) a cumulative allograft survival rate of 92.1% for the 52 consecutive cadaver renal allografts at 18 months; (C) a cumulative allograft survival rate of 100% at 18 months for the 24 of 52 renal allografts without delayed graft function following transplantation; and (D) a cumulative allograft survival rate of 86% at 18 months for the 28 of 52 renal allografts with delayed graft function. Of the 4 of 52 who lost their grafts, 2 grafts were removed following discontinuation of immunosuppressive therapy while the remaining 2 had primary nonfunction; and (E) the lack of a requirement for monoclonal or polyclonal antibodies for the treatment of acute rejection episodes in this patient population. These gratifying results compare very favorably with (A) recent reports of the effects of long-term diltiazem therapy and of verapamil used in conjunction with an induction protocol that included Minnesota antilymphocyte globulin in recipients of cadaver renal allografts, and (B) the clinical outcome in many institutions with OKT3/ATG/ALG induction protocols. Whereas the mechanisms involved in the excellent clinical outcome found with the calcium antagonist remain undefined, our results strongly argue for a prospective, randomized and controlled study in which a calcium antagonist-supplemented immunosuppressive regimen is compared with antibody-based induction protocols.

Adult↗
PubMed1992

Positive crossmatches against mandatorily shared kidneys.

From October 1987 through February 1990 approximately 8.5% (29/341) of all donor kidneys shipped under the UNOS Mandatory Sharing Policy were denied to 27 intended recipients due to a positive final crossmatch [XM(+)]. The intended recipients included 18.5% hispanics and 7.4% blacks compared to 2.4% and 1.6%, respectively, for XM(-) recipients (1-3). Further, more were highly sensitized with 81% having a current PRA greater than 10% and 56% with a peak PRA greater than 80% compared to 65% and 14%, respectively, for XM(-) recipients. More importantly, 19/27 (70%) of the recipient candidates may have had irrelevant positive XMs. The XM(+) patients were classified into five categories defined by: I) autoantibodies; II) transfusions in the 2 weeks prior to the availability of the donor; III) the XM technique; IV) highly sensitized regraft candidates with current and peak PRAs greater than 85% and V) antibody to unreported MHC antigens. Of these, 70% may have been denied a transplant due to IgM autoantibodies or the use of XM techniques lacking extensive evaluation. The authors propose that all XM(+) mandatorily-shared kidneys be examined for IgM autoantibody and that kidneys not be denied to potential recipients due to IgM autoantibody. In addition, to minimize exclusions based on positive B-cell XMs, it is proposed that mandatorily-shared kidneys be shared on the basis of the DR subtypes, insofar as is currently practical.

Histocompatibility Testing↗
PubMed1992

Evidence for the association of unexplained pulmonary hypertension in children with the major histocompatibility complex.

BACKGROUND: A link between primary pulmonary hypertension (PPH) and autoimmune disorders has been postulated. To investigate this relation, we performed immunofluorescent antinuclear antibody tests (ANA) and serological human leukocyte antigen (HLA)-A, B, C, DR, and DQ typing on two groups of Caucasian children with unexplained pulmonary hypertension (PHT) and their parents. METHODS AND RESULTS: Group 1 consisted of 17 children with PPH including two patients with familial PPH and three patients with trivial congenital pulmonary to systemic communications. Group 2 consisted of 13 children with advanced PHT and anatomically large congenital pulmonary to systemic communications (PHT + shunt). Both groups had comparably severe pulmonary vascular disease documented by cardiac catheterization. The following statistically significant data (p less than 0.05) were obtained when the study groups were compared with those published for normal controls. Although positive ANAs and varying titers of autoantibodies were found in both groups of children and mothers (not fathers), +ANAs were only significant for the maternal groups. The PPH (group 1) children had increased frequencies of HLA-DR3, DRw52, and DQw2 and decreased DR5, whereas the group 2 (PHT + shunt) children (also their parents) had no statistically significant alterations in any of the DR or DQ alleles. The PPH mothers had decreased DQw3, an allele in linkage disequilibrium with DR5. CONCLUSIONS: These immunogenetic data suggest that childhood PPH appears to be associated with the major histocompatibility complex alleles HLA-DR3, DRw52, and DQw2. This newly found correlation of juvenile PPH with these alleles adds this disease to the DR3+ group of autoimmune diseases. Further studies are needed to determine whether there is also an immunological or autoimmune component in some children with PHT + shunt lesions because this group lacked an HLA association.

Adult↗
PubMed1992

Familial pulmonary hypertension: immunogenetic findings in four Caucasian kindreds.

A postulated association between primary pulmonary hypertension (PPH) and autoimmune diseases prompted this study. To see if autoantibodies and an association with the major histocompatibility locus (MHC) accompany the familial form of pulmonary hypertension (PHT), we determined human leukocyte antigen (HLA)-class I (A,B,C) and HLA-class II (DR,DQ) typing serologically, serum immunoglobulin (Ig) isotypes, and antinuclear (ANA)-autoantibodies in three families in which more than one member had PPH (FPPH) and in a fourth family with PPH and PHT associated with congenital heart disease. The three FPPH families had 15 PPH + members, eight (in whom the alleles were determined or could be inferred) typed for HLA-DRw52 and seven for HLA-DR3,DRw52,DQw2. These three families each had one PPH+,DR3+ member, with an immunoglobulin isotype deficiency, one with IgA and two with mild IgG. The fourth family differed in that both the patient and asymptomatic relatives had varying autoantibodies and different HLA associations. This family had an anti-centromere+ child with PHT and a congenital heart lesion, a mother who died of PPH, and asymptomatic ANA+ relatives (father anti-Sm+/anti-RNP+; autoantibodies unknown in fraternal twin sister and in maternal grandmother). HLA typing showed that the proband and her fraternal twin sister received DR5,DRw52,DQw3 from their father whereas the proband received DR4,DRw53,DQw3 from the mother and her sister received DR2,DQw1. In summary, three FPPH families had multiple PPH+ members who lacked autoantibodies and typed for HLA-DR3,DRw52,DQw2, whereas a fourth family with familial PHT had PHT+ and PHT- members with autoantibodies and different HLA associations.

Adolescent↗
PubMed1991

The generation and characterization of human monocyte hybridomas.

Fusion of interferon-gamma activated peripheral blood monocytes to a mutagenized hypoxanthine-guanine phosphoribosyltransferase (HGPRT)-deficient U937 parent line was performed resulting in the generation of a series of unique cloned monocyte hybridomas. These cell lines were proven to be true hybrids by the acquisition of donor class I antigens as well as other donor derived chromosomes. In addition, novel functional characteristics were observed including secretion of specific monokines and the acquisition of phagocytic capabilities. The ability to generate immortalized human monocyte hybridomas will allow for more in depth analysis of monocyte subpopulations and dissection of specific monocyte functions.

Analysis of Variance↗
PubMed1991

Selective IgA deficiency, IgG subclass deficiency, and the major histocompatibility complex.

Here we have examined the connection between IgA deficiency, IgG subclass deficiency, and the absence of alleles of complement C4, and show that IgA deficient subjects who have IgG subclass deficiencies may also have an increased frequency of C4 null alleles. In our group, we found an increased incidence of HLA B38 which might reflect the ethnic composition of the patients tested. While family studies are of primary importance to assess the relationships between histocompatibility antigens and immune deficiency, these studies are complicated by the observation that C4 null alleles are not always inherited with the humoral defect.

Adult↗
PubMed1991

Minimal sensitization and excellent renal allograft outcome following donor-specific blood transfusion with a short course of cyclosporine.

UNLABELLED: A new protocol of donor-specific blood transfusion under cyclosporine coverage was developed and examined for immunologic consequences and clinical efficacy in recipients of one- or zero-HLA-haplotype-matched renal allografts. Between 1985 and 1989, 75 recipients were transfused with 100 ml of stored whole blood at 1, 8, and 15 days of its storage from either one-HLA-haplotype-matched related donors (n = 65, 33 from their parents, 30 from siblings, and 2 from offspring) or from zero-HLA-haplotype-matched donors (n = 10, 7 from spouses and 3 from siblings). During DST, all recipients received cyclosporine, 6 mg/kg/day, starting a day before and finishing a week after DST (23 days). Recipients were monitored by donor-specific mixed lymphocyte culture responses before and after DST, and serially for antibodies by fluorescence activated cell sorter analysis and by standard complement-dependent lymphocytotoxicity assay. Following DST with CsA, only 3 of 75 patients (4%) were sensitized against the blood donor. This rate is considerably lower, albeit statistically not significantly, compared with the 10% rate found in 30 recipients who had received DST without CsA in our previous study. Repeat MLC studied one to two months after DST (the day before transplant) were significantly increased compared with pre-DST (stimulation index: mean +/- SEM; 10.3 +/- 1.4 to 15.8 +/- 2.8, P = 0.004, and relative response: 40.9 +/- 5.1% to 49.8 +/- 5.5%, P = 0.003). Since the stimulation index with controls did not change after DST (23.4 +/- 2.9 to 26.2 +/- 3.3), enhanced MLC responses appear to be donor-specific. The changes in MLC responses did not correlate with the number of blood transfusion received prior to DST, the number of rejection episodes, or graft outcome. Fifty-seven recipients underwent a kidney transplant from their one-HLA-haplotype-matched blood donors within two to three months after DST. All 10 recipients of zero-haplotype-matched donors were also successfully transplanted from their respective blood donors. The graft survival rates were at least 90% at two years in both groups. IN CONCLUSION: (1) 100 ml of stored whole-blood DST, three times at weekly intervals with a short course of CsA is minimally sensitizing but effective in enhancing graft survival; (2) this protocol could be used in donor-recipient pairs who do not share a haplotype; and (3) DST with CsA elicits augmentation of donor-specific MLC responses.

Adolescent↗