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I I Doxiadis

Publications and source records attributed to I I Doxiadis.

At least 19 recordsLinked to original sources
PubMed2001

Permissible and immunogenic HLA-A mismatches: cytotoxic T-cell precursor frequencies reflect graft survival data.

Analysis of the in vivo immunogenicity of single HLA mismatches, in the context of a patient's own human leukocyte antigen (HLA) phenotype, has been used to define permissible and immunogenic HLA mismatches. Kidney graft survival in the case of permissible mismatches was similar to that of completely HLA matched combinations, whereas immunogenic mismatches lead to a significantly poorer graft survival. The present study tested whether such permissible and immunogenic HLA mismatches are reflected in the in vitro cytotoxic T-lymphocyte (CTL) allorepertoire. Limiting dilution experiments were performed to analyze the number of precursor CTL directed against individual HLA class I antigens. In general, the frequency of CTLp directed against permissible HLA-A antigens (n = 70, mean frequency 27 CTLp per million peripheral blood lymphocytes [PBL]) was found to be significantly lower compared with the CTLp directed against immunogenic HLA-A antigens (n = 73, mean frequency 59 CTLp per million PBL). The difference was found both in healthy individuals and a population of renal transplant candidates. These results were confirmed by a retrospective analysis of CTLp frequencies performed between partly mismatched unrelated bone marrow donors and their potential recipients. In conclusion, on the population level the permissible and immunogenic HLA-A mismatches are indeed reflected in the CTL allorepertoire. However, due to the big overlap of the CTLp frequencies in these populations, the permissible or immunogenic nature of a mismatch for a particular patient should be determined on an individual basis.

Cells, Cultured↗
PubMed2001

Protective and susceptible HLA polymorphisms in IgA nephropathy patients with end-stage renal failure.

Idiopathic immunoglobulin A (IgA) nephropathy is characterised by an extreme variability in clinical course, leading to end-stage renal failure in 15-20% of adults. This subgroup of patients with IgA nephropathy is usually included in the waiting lists of organ exchange organisations. The frequency of HLA-A,B,DR antigens of this subset of IgA nephropathy patients was calculated and compared to controls. The antigens HLA-B35 and DR5 were significantly increased in the patients with relative risk values of 1.385 and 1.487, respectively. The antigens HLA-B7, B8, DR2, and DR3 were found in a significantly lower frequency in the patients as compared to the controls. The relative risk (RR) values ranged between 0.695 and 0.727. Consequently, the haplotypes HLA-A1, B8, DR3, HLA-A3, B7, DR2, HLA-A2, B7, DR2 together with HLA-A1, B15, DR4, HLA-A9, B12, DR7, and HLA-A10, B18, DR2 were found to be protective with RR values ranging from 0.309 to 0.587. The only susceptible haplotype observed was HLA-A2-B5, DR5 (RR=2.990).

Gene Frequency↗
PubMed2001

Determination of the frequency of HLA antibody secreting B-lymphocytes in alloantigen sensitized individuals.

Sera from prospective transplant patients are usually screened for HLA antibodies prior to transplantation, but presently available tests do not permit quantification of the humoral alloantigen directed response. We adapted a culture system for isolated human B-lymphocytes to assay the secretion of HLA-antibodies on a single cell basis. B-cell supernatants were screened for HLA antibodies by complement dependent cytotoxicity. The assay assigns precursor frequencies for HLA-alloantibody secreting B-lymphocytes (BCPFs), and simultaneously allows for dissection of the humoral alloantigen directed response into its monoclonal components. The lymphocytes of 15 HLA-seropositive multiparous women that were used to validate the assay, were found to contain HLA-BCPFs ranging from 0 to 123 per 10(6) B-lymphocytes (mean: 43 +/- 45 per 10(6) B-lymphocytes). The HLA-specificities of antibodies in the B-cell supernatants were in agreement with serum specificities. Genuine HLA reactivity of B-cell supernatants was confirmed using an ELISA with purified HLA class I antigens. When applied to lymphocytes of patients on transplant waiting lists, the present assay may enable the unraveling of serum specificities in their components, thus supplementing HLA antibody serum screening data.

Antibody Specificity↗
PubMed2000

Cross-reactive group matching does not lead to a better allocation and survival of donor kidneys.

BACKGROUND: In cadaveric renal transplantation HLA-A, -B, -DR matching of donor and recipient is beneficial for graft survival. However, allocation based on HLA matching seems to favor recipients with more frequently occurring HLA antigens. In this study we investigated whether matching on the basis of cross-reactive groups (CREGs), defined according to the United Network for Organ Sharing (UNOS), would be a good alternative for the allocation of kidneys without negatively influencing graft survival. Theoretically, this approach would provide more recipients with an immunologically well-matched donor organ. METHODS: The influence of CREG matching on graft survival was studied in univariate analyses using the Eurotransplant database. RESULTS: No beneficial effect of CREG matching was observed, whereas a significant HLA matching effect was observed in the 0 CREG mismatched donor/ recipient combinations. Only in the small subgroup with 1 MM for HLA-A, -B and 0 MM for HLA-DR, a significantly better survival was observed, when this mismatch belonged to the 0 or 1 MM CREG group versus two or more MM CREG group. However, this subgroup concerns only 8% of the transplants performed. CONCLUSIONS: In contrast to other reports, our study showed that HLA matching is by far more beneficial than CREG matching. In the homogenous Eurotransplant population, adjusting the matching criteria toward CREG matching would not lead to an improved graft survival.

Cross Reactions↗
PubMed2000

Determination of acceptable HLA mismatches in highly sensitized patients by soluble HLA class I ELISA inhibition.

BACKGROUND: Acceptable HLA mismatches for highly sensitized patients are determined so as to increase their chances of receiving transplants. The disadvantage of the current procedures is that the antibody reactivity of the patients' sera is tested against HLA antigens expressed on cells or HLA antigens isolated from cell lysates. Therefore, two (homozygous for HLA-A and -B) to four (heterozygous for HLA-A and -B) different HLA class I antigens are present in the test. This might cause reactivity toward nonacceptable mismatches to mask the determination of acceptable mismatches. METHODS: Recently we observed that the detection of soluble HLA class I antigens is inhibited by HLA-specific antibodies. In the present study, inhibition of soluble HLA-specific ELISAs (anti-soluble HLA-A2, -B7, -B12) was evaluated as a tool used to determine acceptable mismatches. The results were compared with current determination of acceptable mismatches (which is by complement-dependent cytotoxicity and/or fluorescence-activated cell sorter analysis). RESULTS: In the case of acceptable mismatches determined by conventional methods, sera from the patients were not interfering in these ELISAs, whereas in the case of nonacceptable mismatches (thus specific antibodies), significant inhibition was observed in most instances. Among the nonacceptable mismatches, the test showed significant inhibition in 20 of 24 cases, whereas among acceptable mismatches, no inhibition was observed (in eight of eight), indicating the lack of specific antibodies. CONCLUSIONS: In highly sensitized patients, the introduction of soluble HLA-specific ELISAs is of additional and confirmatory value for the determination of acceptable mismatches. The major advantage of this approach is that antibody reactivity is tested against single antigens only.

Antibodies↗
PubMed2000

Correlation between oral sex and a low incidence of preeclampsia: a role for soluble HLA in seminal fluid?

The involvement of immune mechanisms in the aetiology of preeclampsia is often suggested. Normal pregnancy is thought to be associated with a state of tolerance to the foreign antigens of the fetus, whereas in preeclamptic women this immunological tolerance might be hampered. The present study shows that oral sex and swallowing sperm is correlated with a diminished occurrence of preeclampsia which fits in the existing idea that a paternal factor is involved in the occurrence of preeclampsia. Because pregnancy has many similarities with transplantation, we hypothesize that induction of allogeneic tolerance to the paternal HLA molecules of the fetus may be crucial. Recent data suggest that exposure, and especially oral exposure to soluble HLA (sHLA) or HLA derived peptides can lead to transplantation tolerance. Similarly, sHLA antigens, that are present in the seminal plasma, might cause tolerance in the mother to paternal antigens. In order to test whether this indeed may be the case, we investigated whether sHLA antigens are present in seminal plasma. Using a specific ELISA we detected sHLA class I molecules in seminal plasma. The level varied between individuals and was related to the level in plasma. Further studies showed that these sHLA class I molecules included classical HLA class I alleles, such as sHLA-A2, -B7, -B51, -B35 and sHLA-A9. Preliminary data show lower levels of sHLA in seminal plasma in the preeclampsia group, although not significantly different from the control group. An extension of the present study is necessary to verify this hypothesis.

Deglutition↗
PubMed2000

In vitro CTL precursor frequencies do not reflect a beneficial effect of cross-reactive group (CREG) matching.

Adjustment of histocompatibility-based allocation criteria in kidney transplantation from HLA matching to matching on the basis of cross-reactive groups (CREG), was recently suggested to be a good alternative to transplant with more "well-matched" kidneys, without negatively influencing graft survival. Because graft rejection is often mediated by cytotoxic T cells (CTLs), we investigated whether a beneficial effect of CREG matching is reflected in vitro by lower CTL precursor frequencies (CTLpf). Therefore, CTLpf were determined in a group of healthy individuals and analyzed with respect to the number of HLA and CREG mismatches. A clear correlation was found between the number of HLA mismatches and the CTLpf, that is, the lowest mean frequency in case of 0 HLA-A, B mismatches (66 CTL precursors per 10(6) cells) and the highest in combinations with 4 HLA mismatches (mean = 303 CTLp/10(6) cells). The situation was different in the case of CREG mismatches. Although the highest frequency was found in the group of 4 CREG mismatches, no significant differences were observed between 0, 1, and 2 CREG mismatches. High CTLpf, up to 430/10(6), were even seen in the case of 0 CREG mismatches. Also within a well-defined group of single HLA-A or HLA-B mismatches no difference in CTLpf were observed between the subgroups with 0 vs. 1 CREG mismatches. The present study showed that in vitro the CTLpf correlates better with HLA than with CREG matching. These data are consistent with findings reported by several groups that matching for the CREG does not benefit transplant outcome.

Cross Reactions↗
PubMed2000

Donor-derived soluble HLA plasma levels can not be used to monitor graft rejection in heart transplant recipients.

OBJECTIVE: Increased levels of both donor- and recipient-derived HLA class I molecules (sHLA-I) can be found in serum or plasma of transplanted patients during rejection. Earlier data indicate that levels of donor-derived sHLA-I (dsHLA-I) correlate better with graft rejection than total sHLA Class I (Zavazava N, Kraatz E, Gassel AM, Muller-Ruchholtz W. Plasma MHC class I expression in cardiac graft patients: donor-specific soluble antigen in a pre-sensitized graft patient. Transplant Proc 1991;23:2258-2260; Claas FHJ, Jankowska-Gan E, DeVito LD, et al. Monitoring of heart transplant rejection using a donor-specific soluble HLA class I ELISA. Hum Immunol 1993;37:121). Therefore, quantifying donor-derived soluble counterparts of HLA Class I (sHLA-I) in the plasma of the recipient may offer a new possibility for non-invasive monitoring of rejection after organ transplantation. METHODS: In an extended study with 34 heart transplant recipients, we used sHLA-I specific ELISAs to monitor donor-derived soluble sHLA-A2, -A3, -A9, -B7, -B12 and B51. RESULTS: The assays were sensitive enough to detect dsHLA Class I in plasma of the recipients. However, the levels of sHLA were not found to be a useful tool for monitoring rejection. Rejection was often associated with low levels of donor sHLA. The recent finding that antibodies can inhibit the detection of sHLA molecules might explain this discrepancy. In order to test this hypothesis, patient sera were screened for the presence of anti-HLA antibodies and the results were related to the donor-derived sHLA levels. Only in four out of 34 patients HLA Class I specific antibodies could explain the low sHLA levels during rejection. CONCLUSIONS: In heart transplantation increased donor-derived sHLA levels are not a suitable marker for rejection and that antibody formation can not explain these results. Therefore, monitoring rejection episodes on the basis of donor-derived soluble HLA molecules is not a realistic approach to decrease the number of biopsies after heart transplantation.

Animals↗
PubMed2000

Identification of two new alleles HLA-DRB1*0312, DRB1*0432 and of a DRB3-negative DRB1*1313-positive haplotype.

Two new HLA-DRB1 alleles were identified in the course of routine class II molecular typing in Dutch Caucasoid. HLA-DRB1*0312 is similar to *03011 except for codon 57 (GAT-->AGC). DRB1*0432 is similar to *0413 but with a mutation at position 215, changing codon 72 (CGG-->CAG; Arg-->Gln). This sequence has never before been identified at this position. A DRB3-negative DRB1*1313 haplotype was identified in an individual from Indonesia. Monoclonal antibodies against DR52 were nonreactive with lymphocytes of this individual. The DRB1*1313-DRB3-negative haplotype probably represents a recombination of DRB1*13 and *08 haplotypes where the sequences telomeric of HV1 are derived from the DRB3-negative DRB1*0803 haplotype.

Alleles↗
PubMed2000

HLA-C expression on platelets: studies with an HLA-Cw1-specific human monoclonal antibody.

BACKGROUND AND OBJECTIVES: The expression of HLA-C on the surface of platelets is rarely studied due to the lack of proper alloantisera. We addressed this question using an IgM human monoclonal antibody directed against HLA-Cw1 (VP6G3). MATERIAL AND METHODS: Both flow cytometry and complement dependent cytotoxicity studies were used in the current analysis. RESULTS: The expression of the HLA-Cw1 antigen on platelets is lower than on peripheral blood lymphocytes as shown by flow cytometry. Variation in expression levels between individuals is also observed. Using this antibody in a complement-dependent cytotoxicity assay, we did not observe lysis using platelets as targets, whereas peripheral blood lymphocytes of the same blood donors were adequately lysed. CONCLUSIONS: These results confirm that platelets indeed express HLA-C. Furthermore, the results support the insignificant role of HLA-C in immunological platelet refractoriness.

Antibodies, Monoclonal↗
PubMed2000

The relevance of proficiency testing for laboratories involved in cadaveric organ transplantation and its consequences for graft survival.

Organ exchange organizations such as Eurotransplant allocate organs on the basis of histocompatibility testing results. For this reason it is essential that all data reported by the affiliated laboratories are accurate and reliable. The Eurotransplant Reference Laboratory (ETRL) organizes proficiency testing schemes for the tissue-typing centers of the respective renal transplantation units participating in Eurotransplant. Each year, the ETRL sends out 8 peripheral blood samples of healthy blood donors for serological typing and crossmatching, 16 sera to screen for the presence and definition of HLA alloantibodies and 20 DNA samples for molecular typing to the 49 participating centers. The results are collected centrally and reported back to the participants in an open way. These exercises show that the quality of HLA typing, screening and crossmatching improved significantly over the years. In particular, the introduction of molecular typing for HLA-DR resulted in an increase of reliability. The clinical relevance of a reliable HLA typing was demonstrated in a selected group of transplants, the zero HLA-A,-B,-DR- mismatched group. After retyping the donors, 146 of the 3,458 matched transplants appeared to have a mismatch and those transplants had a significantly lower graft survival rate. A continuing problem, however, is the result of screening for panel reactive antibodies (PRA), where the percentage PRA reported for each serum varies significantly from center to center. The results indicate that the use of a PRA value for classification of patients and allocation of organs should be revisited.

Cadaver↗
PubMed1999

Eurotransplant randomized multicenter kidney graft preservation study comparing HTK with UW and Euro-Collins.

The aim was to evaluate the effect of HTK compared to UW and Euro-Collins (EC) on the initial graft function and long term graft survival in two prospective randomized studies. Only kidneys from heart-beating, kidney-only or kidney + heart donors were eligible for entry. Initial non-function (INF) was defined as the absence of life-sustaining renal function, requiring dialysis treatment on two or more occasions, during the first week after transplantation. To evaluate the contribution of the preservation solutions on INF in relation to other factors, a multivariate, 2-step logistic regression model was used. Randomization was performed between July 1990 and September 1992. The UW-HTK study comprised 342 donors and 611 transplants (UW: 168 donors and 297 transplants, HTK: 174 donors and 314 transplants). In the EC-HTK study 317 donors and 569 transplants were included (EC: 155 donors and 277 transplants, HTK: 162 donors and 292 transplants). INF occurred in 33% of either HTK-(n = 105) or UW-(n = 99) preserved kidneys (P = NS), and in 29% of the HTK-(n = 85) and in 43% of the EC-(n = 119) preserved kidneys (P = 0.001). Multivariate analysis showed no significant influence of the preservation solution on the incidence of INF in the UW-HTK study, but factors contributing to INF were donor age, cause of death, retransplantation, and cold ischemic period. The EC-HTK study showed a significantly higher risk of INF, using EC as preservation, in addition to cold ischemic period and donor quality. The 3-year graft survival of HTK-preserved kidneys was 73%, compared to 68% for UW-preserved kidneys in the UW-HTK study (P = NS); while the 3-year graft survival of HTK preserved kidneys was 70% compared to 67% for EC-preserved kidneys in the EC-HTK study (P = NS). We can conclude that HTK is comparable to UW in its preservative abilities, using kidneys from heart-beating kidney-only donors, whereas EC as renal preservation solution should be avoided.

Adenosine↗
PubMed1999

Anti-HLA antibodies interfere in the detection of soluble HLA class I molecules.

Heart transplant rejection is routinely defined by histological evaluation of endomyocardial biopsies (EMB). As elevated levels of donor derived sHLA (dsHLA) can be detected in the serum of transplanted patients just before or during rejection, quantification of donor specific soluble counterparts of HLA Class I (sHLA-I) in the serum of the recipient may be a new way for non-invasive monitoring of graft rejection. However, not all patients show an increase of dsHLA at time of rejection. A reason for this might be that anti-donor-HLA antibodies, which are formed by the patient, form complexes with donor sHLA-I molecules. This masking or blocking of sHLA-I binding sites might cause false-negative results of tests detecting donor specific sHLA. Using HLA-antigen specific ELISA tests we could demonstrate that most anti-HLA antibodies block the detection of sHLA antigens in plasma, even in high dilutions of the antibody when the antibodies were not detectable in a CDC test. In general, HLA-antigen specific antibodies block the detection of sHLA molecules, while broadly-reactive antibodies, recognizing another epitope on the molecule, do not. The implication of these findings is that more than one dsHLA allotype within one patient should be tested to monitor graft rejection. In addition, sHLA monitoring must be combined with an HLA-antibody screening.

Animals↗
PubMed1999

In vitro reactivity of allospecific cytotoxic T lymphocytes does not explain the taboo phenomenon.

Matching for human leucocyte antigens (HLA) is important for graft survival in kidney transplantation. Nevertheless, most patients receive a kidney graft with multiple HLA mismatches. Some of these mismatches seem to be more harmful than others. By studying the effect of single HLA mismatches in the context of the patients' own HLA, we have previously identified donor/recipient combinations with a significantly higher incidence of early graft failure, the so-called taboo combinations. In the present study we investigated whether a higher cytotoxic T lymphocyte (CTL) response towards taboo mismatches may be involved in this phenomenon. CTL reactivity was determined both in taboo and control combinations by in vitro CTL precursor assays, using peripheral blood mononuclear cells and proximal tubular epithelial cells as target cells. Inhibition studies with CD8-antibody as well as Cyclosporin A were performed to identify high avidity and primed CTLs. Furthermore, in committed CTLp assays indirect recognition of the taboo mismatch was tested using synthetic peptides. The CTL precursor frequencies in taboo combinations were always lower than the CTL precursor frequencies in control combinations. No difference in avidity and activation status of the CTLs could be detected when taboo combinations were compared with the controls. In the committed CTLp assays no reactivity towards any of the synthetic peptides was observed. The significantly poorer graft survival of taboo combinations cannot be explained by a higher number of donor-specific CTLs. Furthermore, the avidity or activation status of these CTLs does not provide a clue to the taboo phenomenon.

Cytotoxicity Tests, Immunologic↗
PubMed1999

Sharing cross-reactive groups of MHC class I improves long-term graft survival.

BACKGROUND: Renal transplant loss from chronic rejection remains substantial. To increase our understanding of this syndrome, we identified risk factors predicting late graft loss, with a special emphasis on the impact of human lymphocyte antigen (HLA) matching. METHODS: We studied all 654 cadaveric kidney transplants performed in our center between 1983 and 1996 that had survived for more than six months. Eighty-two transplants, lost because of chronic rejection, were used as the outcome variable. The influence of HLA mismatches and shares on long-term graft survival was evaluated at the level of private antigens and cross-reactive groups (CREG) of multiple histocompatibility complex (MHC) class I. HLA and other recipient, donors and transplant parameters were studied using univariate and multivariate Cox regression analysis. RESULTS: The cohort had a mean number of 1.9 HLA mismatches. Because of the homozygosity of HLA antigens, HLA mismatches were not reciprocal to shares. CREG and HLA-A-B mismatches had a relative risk for graft loss of 1.19 (95% CI, 0.97 to 1.45) and 1.05 (0.84 to 1.32) per mismatch. In contrast, the relative risk per shared CREG and broad HLA-A-B antigen was 0.76 (0.63 to 0.92) and 0.79 (0.61 to 1.03). Multivariate analysis revealed that individuals sharing less than four CREGs had a relative risk of 2.13 (1.29 to 3.75) for late graft loss. Other independent predictors were a recipient age of less than 50 years, relative risk 1.95 (1.02 to 3.71); a donor age of more than 50 years, relative risk 1.68 (1.01 to 2.80); acute rejection (vascular vs. no rejection), relative risk 3.52 (1.72 to 7.18); proteinuria (dipstick > 1+ vs. negative), relative risk 2.86 (1.29 to 6.35); and a serum creatinine concentration of more than 150 micromol/liter at six months, relative risk 3.41 (1.96 to 5.94). CONCLUSION: We identified several coexisting recipient-, donor-, and transplant-related risk factors for graft loss from chronic rejection. In this well-matched group of renal transplants, HLA mismatches and shares had a nonreciprocal relationship. Sharing of HLA antigens, especially CREG of MHC class I, was associated with improved long-term survival.

Adult↗
PubMed1999

Acceptable HLA mismatches for highly immunized patients.

Highly sensitized patients have developed antibodies against many different HLA antigens due to previous pregnancies, blood transfusions or failed transplants. These antibodies cause a positive crossmatch with almost all potential organ donors. As a positive crossmatch is a contra-indication for transplantation, highly sensitized patients have a low chance of transplantation unless special strategies are introduced. One such strategy is the acceptable mismatch program, which has led to transplantation of more than 300 of these highly sensitized patients within Eurotransplant. Centers are participating in the program on a voluntary basis. Before a patient can be included in this program, extensive antibody screening is necessary to define those HLA-A and -B antigens towards which the patient has never formed antibodies. Organ donor selection is based on complete compatibility with the patients own HLA antigens in combination with the acceptable mismatches. If such a combination is identified, mandatory exchange takes place. Despite the success of the acceptable mismatch program, about 25% of the patients will never receive a donor offer. These are patients with rare HLA antigens or rare combinations of HLA antigens. In the last few years, this group of patients has had the advantage of two additional programs running within Eurotransplant. In the HIT (highly immunized tray) program, sera of highly sensitized patients are sent to the different centers and crossmatched with all ABO compatible donors. In the case of a negative crossmatch, mandatory exchange takes place. Secondly, these patients can benefit from the extra points they receive for their waiting time, high antibody reactivity and rare HLA type in the standard Eurotransplant allocation system. We conclude that the application of these three strategies will lead to a significantly increased transplantation rate of highly sensitized patients.

Cross Reactions↗
PubMed1998

The application of human monoclonal antibodies for monitoring donor derived soluble HLA class I molecules in the serum of heart transplant recipients.

Increased levels of both donor and recipient derived HLA molecules can be found in serum and plasma of transplanted patients during rejection. Recent data suggest that levels of donor specific soluble HLA Class I (sHLA-1) correlate better with graft rejection than total sHLA Class I [1, 2]. Therefore, quantification of donor specific soluble counterparts of HLA Class I in the serum of the recipient may be a new way for non-invasive monitoring of rejection after organ transplantation. Up to now, only a limited number of mouse monoclonal antibodies (alpha HLA-A2, and alpha HLA-B7) has been used in enzyme linked immunosorbent assays (ELISAs) to detect donor specific HLA molecules in the plasma of transplant recipients. To monitor other donor-recipient combinations, we tested some of our HLA Class I specific human monoclonal antibodies, routinely used in complement dependent cytotoxicity, for their suitability in ELISA based assays. In the present model system, we used alpha HLA-A9 (BvK5C4) or alpha HLA-A3 (OK2F3) hybridoma-supernatant to set up a sHLA-A9 and sHLA-A3 specific ELISA. In a pilot study we show that these assays were sensitive enough to detect an increase of donor specific sHLA-I during rejection in the plasma of two heart transplant recipients. Use of a large set of human hybridoma's will enable monitoring most recipient/donor combinations in the near future.

Animals↗