襄阳地区血小板输注无效患者抗体检测及分析

目的探讨襄阳地区血小板输注无效患者血小板抗体阳性率及相关因素,为提高输注疗效提供依据。方法对襄阳地区68例血小板输注无效患者和同期60例健康体检人员进行血小板抗体筛检,并对血小板抗体阳性患者进行血小板抗体鉴定,分析人类白细胞抗原(HLA)、人类血小板抗原(HPA)抗体阳性率。结果研究组PLT抗体阳性率29.4%,弱阳性率8.8%,阴性率61.8%;其中HLA抗体阳性率23.5%,HPA抗体阳性率10.3%,HLA抗体合并HPA抗体阳性率4.4%;女性PLT抗体阳性率(31.6%)高于男性(26.7%),但无显著性差异(P0.05);随着输血次数增加,PLT抗体阳性率增高(χ2=4.146,P0.05),当输血次数为4-6次时,增高幅度最大。结论襄阳地区血小板输注无效患者中PLT抗体以HLA抗体为主,其次为HPA抗体。PLT抗体阳性率随输血次数增加而增加,并且与性别无关。     

探究反复输血治疗的血液病患者行血小板抗体筛查及配型对预防免疫性输注无效的临床意义

目的探讨血液病患者反复输血治疗后血小板抗体的产生情况以及交叉配型对血小板输注疗效的影响。方法采用固相凝集法对216例血液病患者进行血小板抗体筛查,将血小板抗体阳性患者随机分为配合性输注(28例)和随机输注(25例),比较两种输注方式的效果。结果 216例血液病患者中共检出血小板抗体53例(24.54%),其中HLA抗体阳性34例(15.74%),HPA抗体阳性12例(5.56%),HLA合并HPA抗体阳性7例(3.24%);有妊娠史患者血小板抗体阳性率(34.48%)高于无妊娠史患者(14.71%),差异有统计学意义(P0.05);血小板抗体阳性率随输血次数增多不断升高;配合性输注输血后1h和24h CCI显著高于随机输注,差异有统计学意义(均P0.05)。结论反复输血血液病患者存在一定比例的血小板抗体阳性,本地区血小板抗体以HLA抗体为主,随输血次数增多血小板抗体阳性率不断升高,交叉配型可提高血小板的输注效果,避免血液资源的浪费。     

血小板配型检测体系的建立及应用效果观察

目的寻找配型血小板输注、防止血小板输注无效的便捷方法。方法对92例需要反复输注浓缩红细胞、血小板血液病患者采用简易致敏红细胞血小板血清学技术(SEPSA)的检测,研究患者输血次数与血小板抗体产生的关系及血小板抗体的性质,并对血小板抗体阳性的病人建立档案,与血站固定的献血者的血液进行血小板配型实验,建立一个患者尽量与多个献血者配合相合的对应关系,并记录存档。对需要再次输注血小板的患者,给予相合的血小板。结果92例患者血小板抗体阳性25例,阳性率27.2%,其中HLA抗体19阳性例,HLA和HPA同时阳性4例,KPA阳性1例;血小板抗体阳性率与输血次数有明显的正相关。对12例血小板抗体阳性的患者共进行了35例次交叉配型血小极输注,CCI无效率分别为:配型前69.0%,配型后22.9%(x2=18.46,P<0.01)。结论在92例患者中,对产生同种抗体的部分患者,及时进行血小板配型并建立档案,加强医院与血站的信息沟通,可明显提高血小板的输注效率。     

血小板输注无效患者的供者筛选策略及临床研究

目的探讨解决血小板输注无效的途径，改善血小板输注效果。方法对36例血小板输注无效患者先进行HLA抗体与HPA抗体检测，然后分别在血小板供者库中找到HLA—I类位点3个以上抗原相合的供者，进行血小板交叉配合试验。结果365例PTR患者中HLA抗体和HPA抗体检出阳性率分别为75．0％和8．3％，HLA与HPA联合抗体检出阳匪率为16．7％。对27例仅有HLA抗体的患者选择HLA—I类位点3个以上抗原相合的供者，其血小板输注有效率为96．3％，对3例有HPA抗体的患者采用血小板交叉配合试验，其血小板输注有效率为100．0％。对6例有HLA与HPA联合抗体的患者，选择HLA—I类位点3个以上抗原相合的供者，进行血小板交叉配合试验，其血小板输注有效率为67．3％。结论对PTR患者进行抗体筛查，选择HLA相合的供血者及血小板交叉配合试验十分重要，是解决PTR的有效途径。     

造血干细胞移植同种免疫抗体对血小板输注的影响

目的了解造血干细胞移植前同种免疫性抗体阳性患者术后血小板的输注情况。方法1)检测HSCT术前和术后HLA抗体、血小板特异性(HPA)抗体。2)移植术后采用补体依赖淋巴细胞毒试验(CDC)配合血小板输注,观察输注后患者的血小板增加修正值(CCI)。结果1)术前HLA抗体阳性9名,强度为22%-72%,HPA抗体阳性1名;术后HLA抗体阳性8名,强度为15%-45%,HPA抗体阴性9名;2)输注术后血清CDC配合血小板9名,其中4名达到血小板有效输注;5名血小板无效输注;3)5名无效输注患者输注术前和术后血清CDC配合血小板,其中4名达到血小板有效输注,与其输注术前血清CDC配合血小板CCI值相比较,差异有统计学意义(P<0.05),1名术前HPA抗体阳性患者仍为血小板无效输注。结论HSCT前应监测患者HLA和HPA抗体及其强度,术前保存HLA抗体强度较高血清,有助于术后筛选有效的血小板供者。     

血小板抗体检测与患者血小板输注效果的分析

目的分析血小板抗体检测与患者血小板输注效果的关系。方法用固相红细胞吸附试验(sPRA)对348名反复多次输注血小板的患者,进行了血小板抗-HLA和抗-HPA的检测,分析抗体产生规律,并观察抗体阳性患者的血小板输注效果。结果 348名反复输血小板患者检测出血小板抗体阳性率63.79%,其中抗-HLA阳性107例,阳性率30.75%;抗-HPA 24例,阳性率6.89%;其中抗-HLA合并抗-HPA 91例,阳性率26.15%。抗体阳性率与血小板输注次数成正比(P<0.05),且与输注效果间的差异有统计学意义(P<0.05)。结论血小板输注次数越多,血小板抗体的产生几率越大;血小板抗体的产生直接影响血小板输注效果。     

单采血小板输血反应调查及其输注无效解决策略

目的调查单采血小板输血反应发生率,并探讨血小板输注无效解决策略,以提高血小板输注的安全性和有效性。方法调查上海地区5家临床医院单采血小板输注情况,统计紫癜、发热、寒颤等输血反应发生比例,并对这些发生输血反应的样本进行HLA和HPA抗体筛选。对抗体阳性患者进行HLA和HPA分型,并从建立的已知HLA和HPA型单采血小板供者库中寻找HLA或HLA交叉反应抗原组(CREG)和HPA相同供者,进行血小板同型(或配合型)输注。结果调查期间5家医院共输注单采血小板2194袋,发生各类输血反应53例,输血反应发生率2.42%,HLA和HPA抗体检测阳性率为24.5%。施行同型(或配合型)输注3例,其中1例24h血小板回收率超过80%。结论与手工混合血小板相比较,输注单采血小板可显著降低输血反应的发生。临床血小板同型(或配合型)输注策略,对提高血小板输注的安全性和有效性有着积极意义。     

哈尔滨地区血小板输注无效患者的抗体鉴定与分析

目的探讨与分析哈尔滨地区免疫性血小板输注无效患者血小板抗体类型。方法对2017年11月-2018年6月的38例临床血小板输注无效的交叉配型阳性的患者,采用PAKPLUS试剂盒进行血小板特异性抗体鉴定,分析患者HLA抗体和HPA抗体分布情况。结果 36例患者出现抗体阳性,其中单一HLA-Ⅰ类抗体阳性5例(13.9%),单一HPA抗体阳性3例(8.3%),HLA-Ⅰ类抗体和HPA抗体均阳性28例(77.8%);2例未检出HLA-Ⅰ类抗体和HPA抗体。31例HPA抗体阳性中,患者血小板膜糖蛋白抗体鉴定结果为,GPⅡb/Ⅲa抗体26例(72.2%),GPⅠa/Ⅱa抗体23例(63.9%), GPⅠb/Ⅸ抗体19例(52.8%),GPⅣ抗体17例(47.2%)。抗体阳性患者中女性21例,男性15例;女性HLA抗体阳性率高于男性,女性HPA抗体阳性率低于男性,但差异无统计学意义。结论 PTR患者中血小板抗体以HLA-Ⅰ类抗体合并HPA抗体为主。     

血液病患者血小板输注无效病因探析

目的探讨血液病患者血小板输注无效原因并评估血小板抗体在血小板输注中的影响。方法选取125例血液病患者并按病种进行分组,采用酶联免疫吸附(ELISA)方法检测血小板抗体及其特异性。结果 125例血液病患者血小板输注无效率为28.0%(35/125),非免疫因素占60.0%(21/35),免疫因素占40.0%(14/35),其中HLA抗体阳性12例,HPA抗体阳性2例,未发现CD36抗体。在35例血小板输注无效患者中,急性白血病占62.9%。血小板抗体阳性率与血小板输注次数有关,与患者的民族、性别、血型无关。结论血小板输注无效主要由非免疫因素引起的,免疫因素以HLA抗体为主。血小板输注无效与患者所患疾病、输注次数、各类并发症有关。     

血小板抗体筛查在多次输血的白血病患者中的应用分析

目的 探讨68例白血病患者血小板抗体的产生与血小板输注次数的关系;血小板输注效果与血小板抗体之间的关系。方法 检测68例白血病患者单采血小板输注前后外周血小板计数;以24h CCI值判断血小板输注效果;血小板抗体筛查采用固相凝集法。结果 68例输注单采血小板的患者中共检出抗体阳性13例,阳性率为19.1%,对照组阳性率2.8%,差异具统计学意义;血小板输注次数8次时,血小板抗体的阳性率为(53.3%)分别与输注次数3次组(抗体阳性率8.3%)和输注3-8次组(抗体阳性率10.3%)比较,差异均具统计学意义(P0.05);血小板抗体阴性患者的血小板输注无效率(32.7%)与血小板抗体阳性患者的输注无效率(69.2%)比较,差异具统计学意义(P0.05)。结论 随着血小板输注次数的增多血小板抗体检出率明显增高,与输注次数成正相关;血小板抗体阳性与血小板输注无效有相关性。     

血小板输注无效患者血小板同种抗体及血小板特异性糖蛋白抗体表达的研究

目的 探讨血小板输注无效与血小板同种抗原或血小板特异性抗原的相关性.方法 选择65例临床确诊血小板输注无效患者作为研究对象,应用酶联免疫吸附实验(ELISA)方法检测血清、血小板洗脱液中血小板特异性抗体;应用HLA抗体特异性检测试剂盒,对组合反应性抗体(PRA)阳性的患者进行HLA抗体特异性分析;用HPA分型试剂盒检测8个血小板同种抗原系统HPA-1、2、3、4、5、6、9、15;用HLA分型试剂盒对HLA-A/B抗原进行基因分型.结果 65例患者HLA-A/B抗原,HPA-1、2、4、5、6、9、15抗原的基因频率分布与健康献血员比较差异无统计学意义.HPA-3a、3b抗原频率分别为0.65、0.35,与健康献血员比较差异有统计学意义(P＜0.05).65例患者中HLA抗体单独阳性24例(36.9%),HLA抗体和血小板特异性糖蛋白抗体共同阳性14例(21.5%);HLA抗体和血小板洗脱液特异性糖蛋白抗体共同阳性6例(9.2%),血小板洗脱液特异性糖蛋白抗体阳性13例(20%),HLA抗体、血小板特异性糖蛋白抗体及血小板洗脱液特异性糖蛋白抗体共同阳性4例(6.2%);HLA-A/B特异性抗体中,HLA-A*9抗体占全部抗体的46.2%,HLA-B*40抗体占33.6%.血清血小板特异性抗体以GPⅡb/Ⅲa为主(26.2%),其次为GP Ⅰa/Ⅱa(21.5%),血小板洗脱液中,血小板特异性抗体以GPⅡb/Ⅲa和GP Ⅰb/Ⅸ为主(41.5%).对2例患者进行了遗传学调查,发现产生的血小板特异性糖蛋白抗体和HLA抗体与父母血小板抗原及HLA抗原不相合呈密切相关.结论 血小板输注无效患者中,HLA抗体占主要地位,其次为血小板特异性糖蛋白抗体.     

Antibodies to private and public HLA class I epitopes in platelet recipients

BACKGROUND: Transfusions or pregnancies can cause immunization against private HLA determinants and public epitopes shared by more than one private HLA antigen. HLA antibodies are correlated with febrile transfusion reactions, lower platelet response following platelet transfusion, and an increased rate of renal transplant rejection. Until now, antibody specificities in alloantisera from platelet recipients have been poorly characterized. STUDY DESIGN AND METHODS: Consecutive serum screens from platelet recipients were analyzed for antibodies against private HLA class I antigens and public HLA epitopes using a serum analysis program based on the 2 x 2 table analysis of correlations. Serum screens of highly immunized patients and of patients with new alloimmunization events were reviewed separately. RESULTS: Of the serum screens from 566 platelet recipients, 1577 indicated alloimmunization (panel-reactive antibodies >5%). The program assigned a specificity in 1024 of these screens (64.9%) and at least once in 522 of 566 patients (92.2%). In 267 patients, antibodies detecting public epitopes in the combined A- or B-locus cross-reacting groups were found; other public markers were detected in 39 patients. Patterns of reactivity were remarkably less stable than in patient groups previously studied. In many patients, antibodies with apparent private epitope specificity preceded the identification of antibodies against a shared marker of the same cross-reactive group. However, the disappearance of antibodies (whether or not this was followed by a new antibody against a private or public marker belonging to another cross-reacting group) was also observed. CONCLUSION: The computerized analysis of microlymphocytotoxicity tests enhances the rate of antibody specification in sera from platelet recipients with lymphocytotoxic antibodies. The identified antibodies should be taken into account in the selection of platelet donors. The data confirm and extend previous observations on HLA class I antibodies and elucidate new alloimmunization events.     

Platelet-reactive HLA antibodies associated with low posttransfusion platelet increments:a comparison between the monoclonal antibody-specific immobilization of platelet antigens assay and the lymphocytotoxicity test

BACKGROUND: Platelet-reactive HLA antibodies are a major reason for low posttransfusion platelet increments. The clinical importance and value of the test systems for their in vitro determination is still controversial. STUDY DESIGN AND METHODS: A prospective analysis of HLA antibodies was performed in sera obtained once a week for at least 4 consecutive weeks from 55 patients (female/male, 28/27; age: median, 49 years; range, 18-69) undergoing intensive chemotherapy and in need of prophylactic platelet transfusions. All sera (n = 330) were analyzed by the monoclonal antibody-specific immobilization of platelet antigens (MAIPA) assay and by the standard lymphocytotoxicity test (LCT). RESULTS: In the MAIPA, 24.5 percent of sera (81/330) obtained from 22 patients contained HLA antibodies. These were detected significantly more often by the MAIPA assay than by the LCT (24.5% vs. 8.2%). Fifty-five sera (20 patients) were positive in the MAIPA assay only. In 15 patients, HLA antibodies were transient. In 3 patients, HLA antibodies were detected earlier by the MAIPA assay than by the LCT. Significantly more sera obtained at the time of low posttransfusion platelet increments were positive in MAIPA alone, rather than in both MAIPA and the LCT (44% vs. 17%). CONCLUSION: The MAIPA assay is more sensitive than the standard LCT in detecting platelet-reactive HLA antibodies. These MAIPA-positive/LCT-negative HLA antibodies affect the posttransfusion platelet increment.     

Detection of HLA antibodies by platelet crossmatching techniques

Thirty-seven monospecific HLA antibodies directed against all common HLA-A and -B loci and reactive by the microlymphocytotoxicity assay (LCT) were tested against platelets carrying the corresponding antigen by three platelet crossmatch methods, the platelet immunofluorescence test (PIFT), platelet enzyme-linked immunosorbent assay (P-ELISA), and platelet radioimmunoassay (P-RIA). Positive reactions were obtained with the PIFT in 67 percent, the P-ELISA in 41 percent, and the P-RIA in 49 percent of 85 cell-serum pairs. The same cell-serum combinations gave 49 percent positive reactions in the lymphocyte immunofluorescence test. Three multispecific HLA antisera were positive in nine of nine cell-serum combinations by all four methods. Thirteen transfusions were given to eight patients with known HLA antibodies. All donor-recipient pairs were LCT positive, six were PIFT positive, and seven were PIFT negative. Three of seven PIFT-negative and none of six PIFT-positive transfusions were successful. Thus, platelet crossmatching is less sensitive than the LCT for the detection of complement-binding monospecific HLA antibodies. The platelet crossmatch, however, is able to identify some potentially successful HLA-incompatible donors for patients with multispecific HLA antibodies and limited access to HLA-identical donors.     

血小板输注无效患者体内血小板反应性抗体特异性调查研究

目的探讨血小板输注无效患者体内血小板反应性抗体的发生频率及其特异性。方法对48名血小板输注无效患者,利用MACE法筛查其血清中的血小板反应性抗体,进一步用PAK12诊断试剂MAIPA法鉴定血小板HPA抗体特异性。结果血小板输注无效患者中血小板反应性抗体的总检出率为50%(24/48),其中同种HLA抗体发生率为39.6%(19/48),占所有抗体检出的79.2%,同种HPA抗体的检出率为29.2%(14/48),而其中有64.3%(9/14)是与HLA抗体同时存在。检出的HPA抗体特异性有抗-HPA-3a(n=2),-5a(n=1),-5b(n=1),-2b(n=1),-4b(n=1);同时HPA抗体中有78.6%(11/14)是针对GPⅡb/Ⅲa,Ⅰa/Ⅱa和/或Ⅰb/Ⅸ的多反应性抗体。女性患者中检出抗体的比例55.2%(16/29)高于男性患者42.1%(8/19),但差异没有显著性统计学意义。结论血小板输注无效患者中血小板同种抗体以HLA抗体多见,但HPA抗体并不像之前报道的罕见。与高加索人群PTR患者血小板同种反应性抗体以抗-HPA-5b,-1b为主不同,研究发现中国人群PTR患者HPA同种抗体以HPA-3,-5系统抗体多见,同时检出了HPA-4b,-2b抗体。     

Platelet-specific antibodies in HLA-immunized patients receiving chronic platelet support

BACKGROUND: In HLA-alloimmunized patients, the unexpected failure of HLA-matched platelet transfusions usually raises the suspicion about concomitant platelet-specific antibodies. As the reported frequency of platelet-specific antibodies in multitransfused patients varies widely, the aim of this study was to determine the prevalence of such antibodies in a population of chronic thrombocytopenic patients with HLA antibodies. STUDY DESIGN AND METHODS: From 1985 to 1997, 11,777 determinations of HLA antibodies were performed in 1330 hematologic patients receiving chronic platelet support. Fifty-two patients with HLA alloimmunization that lasted more than 1 month were selected. The search for platelet-specific antibodies was performed by using a monoclonal antibody immobilization of platelet antigens assay, thus allowing the identification of platelet-specific antibodies directed against the platelet glycoproteins (GP) Ib/IX, GPIIb/IIIa, and GPIa/IIa. Specificity of the platelet-specific antibodies was further investigated by using a solid-phase assay with chloroquine-treated platelets. RESULTS: Only 2 (3.8%) of the 52 patients had platelet-specific antibodies. One antibody reacted with an epitope of the GPIIb/IIIa that was present in all the panel platelets, and that probably was an autoantibody. The other was an anti-HPA-5b. CONCLUSIONS: The prevalence of platelet-specific antibodies in patients with HLA alloimmunization is very small. The search for concomitant platelet-specific antibodies would be indicated only when other causes of refractoriness to HLA-matched platelets are ruled out.     

Alloimmunization to platelet-specific antigens on glycoproteins IIb- IIIa and Ib/IX in multiply transfused thrombocytopenic patients

The rate of alloimmunization to platelet-specific antigens associated with platelet glycoproteins (GPs) IIb-IIIa and Ib/IX was studied in 293 multiply transfused thrombocytopenic patients. Antibodies to platelet-specific antigens were measured with a solid-phase assay using platelet GP IIb-IIIa or Ib/IX as the antigenic targets. Nine patients were found to have antibodies to platelet GP IIb-IIIa, and no patients had antibodies to platelet GP Ib/IX. In six of these nine patients, the specificity of the antibody was shown by using GP IIb-IIIa from donors with different platelet-specific antigen phenotypes. In the remaining three patients with antibodies to platelet GP IIb-IIIa, no specificity could be identified. These patients had autoimmune thrombocytopenia in association with lymphoma. The alloimmunization rate to platelet-specific antigens associated with GP IIb-IIIa was 2 percent, whereas the rate of alloimmunization to HLA antigens was 23 percent. Of the patients alloimmunized to HLA antigens, 9 percent also had antibodies to platelet-specific antigens. A poor response to HLA-identical platelet transfusions was observed only in those patients with positive assays in the solid-phase test. These results suggest that the incidence of antibodies to platelet-specific antigens carried on GP IIb-IIIa is low. Platelet-specific antibodies may be found more frequently in patients alloimmunized to HLA antigens than in those not so alloimmunized.     

Heterogeneity of antibody response to human platelet transfusion.

To study the antibody response to human platelet transfusions, nine thrombocytopenia patients with bone marrow failure were given 6 U (3X10(11)) of random platelet concentrates twice a week. Before transfusion, none of the patients had preexisting antibodies detectable with lymphocytotoxicity, platelet aggregation, or capillary leukoagglutination techniques. After receiving 18-78 U of platelets, they became refractory to further transfusions of random platelets and alloantibodies were detectable. Two patterns of antibody response could be identified. In three patients, the sera were not lymphocytotoxic with a panel of standard cells in which all the known HLA antigens in the first and second series were represented at least once. Yet, they caused platelet aggregation with 30, 24, and 60%, respectively, of a donor population studied. The aggregating activities were inhibited by antihuman IgG but not by antihuman IgA or antihuman IgM antiserum. The aggregating antibodies could be absorbed out with donor platelets but not lymphocytes or granulocytes. Antibodies from two of these patients aggregated platelets of their respective siblings matched for both HLA haplotypes. Transfusion of platelets from these two siblings did not increase the platelet count while platelets obtained from aggregation-negative donors did. The sera from the remaining six patients were lymphocytotoxic with 15-100% of the panel of standard cells. They also had aggregating antibodies, which could be absorbed out by both platelets and lymphocytes, suggesting that they were HLA antibodies. These data suggest that the development of platelet-specific antibodies may play an important role in the immunological rejection of isologous platelets, and should be considered in the selection of donors for patients who are refractory to platelets from random donors.     

Platelet alloimmunization after long-term red cell transfusion in transfusion-dependent thalassemia patients

BACKGROUND: The platelet (PLT) alloimminization status after long-term red cell (RBC) transfusion in thalassemia patients was investigated, including antibodies against HLA antigens and PLT-specific glycoprotein antigens. STUDY DESIGN AND METHODS: Blood samples from a total of 60 thalassemia patients who routinely received washed RBCs were tested for the presence of HLA antibodies and PLT-specific glycoprotein antibodies with a commercial enzyme immunoassay kit. All patients were rescreened at a follow-up period of 12 to 15 months. RESULTS: At the first year of study, 19 (31%) patients had HLA antibodies, 13 (22%) had HLA antibodies and PLT-specific antibodies, and 1 (2%) had PLT-specific antibodies. One patient showed weak reactive PLT autoantibody. The follow-up study showed that 7 patients developed HLA antibodies, whereas 1 patient lost HLA antibody activity. Nine patients developed new PLT-specific antibodies, yet 12 patients lost at least one of their PLT-specific antibodies. CONCLUSION: Long-term RBC transfusions can induce PLT alloimmunization, both to HLA antigens and to PLT-specific antigens. The residual PLTs and white blood cells in RBC components could be the sources of immunization. In our thalassemia patients, HLA antibodies likely sustain longer than PLT-specific antibodies.     

The natural history of alloimmunization to platelets

Sixty-three patients have provided evidence that platelets are highly immunogenic even in recipients of potentially immunosuppressive therapy for malignant diseases. Approximately 70 per cent of patients who receive repeated transfusions of platelets from random donors over a prolonged period can be expected to develop lymphocytotoxic antibodies. Antibodies became detectable in one patient ten days after his first exposure to HLA antigens in the form of platelet concentrates, and as early as four days in two patients with prior exposure to HLA antigens. In the most heavily immunized patients, the presence of antibody correlated with poor increments of platelets after transfusion. Patients with prior exposure to HLA antigens are more likely to have antibodies resulting in poor platelet survival. On the other hand, 30 per cent of recipients of repeated platelet transfusions show no tendency to form cytotoxic antibodies.