Workload and procedures used by European data protection authorities related to personal data protection: a cross-sectional study.

OBJECTIVE: Data protection authorities (DPAs) are independent public authorities supervising the application of the data protection law. There is one DPA in each European Union (EU) Member State. Workload and procedures used by European DPAs were analyzed via a cross-sectional study. RESULTS: DPAs from 13 countries participated: Austria, Bulgaria, Croatia, Estonia, Finland, Greece, Italy, Latvia, Liechtenstein, Lithuania, Norway, Romania, and Slovakia. Responding to opinion/guidance requests in DPAs was highly heterogeneous. Procedure types used by DPAs varied, from telephone-based advisory service in Norway to a formal legal opinion in Austria. The deadline for responding to the requests varied considerably in DPAs. The number of opinion/guidance requests sent by data controllers and processors, and the number of opinion/guidance requests and complaints sent by data subjects, increased from 2015 to 2018 when the General Data Protection Regulation (GDPR) came into full effect; it decreased in 2019. Few DPAs organized education about data protection for the research community. In conclusion, the procedures and workload of DPAs in the EU were highly variable. It is important to study these aspects further, as they may assist in tailoring future data protection policies and procedures at the EU level.

Corrigendum to: Post-GDPR survey of data protection officers in research and non-research institutions in Croatia: a cross-sectional study.

[This corrects the article DOI: 10.11613/BM.2021.030703.].

Ethics appraisal procedure in 79,670 Marie Sklodowska-Curie proposals from the entire European HORIZON 2020 research and innovation program (2014-2020): A retrospective analysis.

INTRODUCTION: Horizon 2020 was the most significant EU Research and Innovation programme ever implemented and included the Marie Sklodowska-Curie Actions (MSCA). Proposals submitted to the MSCA actions awere subject to the Ethics Appraisal Procedure. In this work we explored the ethics appraisal procedure in MSCA H2020. METHODS: Using a retrospective analysis of pooled anonymized data, we explored the ethics appraisal procedure on proposals submitted to Marie Sklodowska-Curie Actions (MSCA) during the entire Horizon 2020 program period (N = 79,670). RESULTS: Our results showed that one of the most frequently identified ethics categories was Data protection. We also detected slight differences between applicants' and the ethics reviewers' awareness of ethical issues. Trajectory analysis of all ethics screened proposals appearing on main lists showed that a minimal portion of all screened submissions required additional ethics checks in the project implementation phase. CONCLUSION: Personal data protection is one of the most represented ethics categories indicated among MSCA actions which exhaust ethics assessment efforts and may lead to "overkills" in ethics requirements. Excluding the majority of personal data protection assessment from the ethics assessment, except for parts which are directly related to ethics like "Informed consent procedures", might be necessary in the future. A gap in understanding of ethics issues between applicants and reviewers' points to the necessity to further educate researchers on research ethics issues.

Post-GDPR survey of data protection officers in research and non-research institutions in Croatia: a cross-sectional study.

INTRODUCTION: General Data Protection Regulation (GDPR) focuses on important elements of data ethics, including protecting people's privacy, accountability and transparency. According to the GDPR, certain public institutions are obliged to appoint a Data Protection Officer (DPO). However, there is little publicly available data from national EU surveys on DPOs. This study aimed to examine the scope of work, type of work, and education of DPOs in institutions in Croatia. MATERIALS AND METHODS: During 2020-2021, this cross-sectional study surveyed DPOs appointed in Croatia. The survey had 35 items. The questions referred to their appointment, work methods, number and type of cases handled by DPOs, the sources of information they use, their experience and education, level of work independence, contacts with ethics committees, problems experienced, knowledge, suggestions for improvement of their work, changes caused by the GDPR, and sociodemographic information. RESULTS: Out of 5671 invited DPOs, 732 (13%) participated in the study. The majority (91%) indicated that they could perform their job independently; they did not have prior experience in data protection before being appointed as DPOs (54%) and that they need additional education in data protection (82%). CONCLUSIONS: Most DPOs indicated that they had none or minimal prior experience in data protection when they were appointed as DPO, that they would benefit from further education on data protection, and exhibited insufficient knowledge on basic concepts of personal data protection. Requirements for DPO appointments should be clarified; mandatory education and certification of DPOs could be introduced and DPOs encouraged to engage in continuous education.

Before and after enforcement of GDPR: Personal data protection requests received by Croatian Personal Data Protection Agency from academic and research institutions.

INTRODUCTION: The European Union's (EU) General Data Protection Regulation (GDPR) was put in force on 25th May 2018. It is not known how many personal data protection requests the national authority in Croatia had received before and after GDPR, and how many of those were related to research. MATERIALS AND METHODS: We obtained data from the Croatian Personal Data Protection Agency (CPDPA) about requests/complaints related to personal data protection that were received specifically from academic/research institutions, specifically the number and type of all cases/requests between the years 2015-2019. RESULTS: In 2018, CPDPA had a dramatic increase in the number of requests in the post-GDPR period, compared to the pre-GDPR period of the same year. In 2019, CPDPA received 2718 requests/complaints; less than in the year 2018. From 2015 to 2019, CPDPA received only 37 requests related to research. CONCLUSIONS: Very few requests about personal data protection from academic and research institutions in Croatia were submitted to the national Croatian data protection authority. Future studies could explore whether researchers have sufficient awareness and knowledge about personal data protection related to research, to adequately implement the GDPR regulations.

Ethics assessment in research proposals adopting CRISPR technology.

The rapid and exponential growth of genome editing has posed many challenges for bioethics. This article briefly explains the nature of the technique and the particularly rapid development of Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR) technology. The international and, specifically, European-level systems for assessing the ethical issues consequent on these developments are outlined and discussed. The challenges posed by cases in China are summarized to raise concerns about how a more shared, universally consistent appraisal of bioethical issues can be promoted.

The role of natural killer T cells in costimulation blockade-based mixed chimerism.

Distinct lymphocyte populations have been identified that either promote or impede the establishment of chimerism and tolerance through allogeneic bone marrow transplantation (BMT). Natural killer T (NKT) cells have pleiotropic regulatory properties capable of either augmenting or downmodulating various immune responses. We investigated in this study whether NKT cells affect outcome in mixed chimerism models employing fully mismatched nonmyeloablative BMT with costimulation blockade (CB). The absence of NKT cells had no detectable effect on chimerism or skin graft tolerance after conditioning with 3Gy total body irradiation (TBI), and a limited positive effect with 1Gy TBI. Stimulation of NKT cells with alpha-galactosylceramide (alpha-gal) at the time of BMT prevented chimerism and tolerance. Activation of recipient (as opposed to donor) NKT cells was necessary and sufficient for the alpha-gal effect. The detrimental effect of NKT activation was also observed in the absence of T cells after conditioning with in vivo T-cell depletion (TCD). NKT cells triggered rejection of BM via NK cells as chimerism and tolerance were not abrogated when NKT cells were stimulated in the absence of both NK cells and T cells. Thus, activation of NKT cells at the time of BMT overcomes the effects of CB, inhibiting the establishment of chimerism and tolerance.

CTLA4Ig promotes the induction of hematopoietic chimerism and tolerance independently of Indoleamine-2,3-dioxygenase.

Bone marrow transplantation (BMT) under costimulation blockade induces mixed chimerism and tolerance in rodent models. Recent data, predominantly from in vitro studies, suggest that in addition to blocking the CD28 costimulation pathway CTLA4Ig also acts through upregulating the tryptophan-catabolizing enzyme indoleamine-2,3-dioxygenase (IDO). Here we demonstrate that even though CTLA4Ig is critically required for the induction of chimerism and tolerance in a murine model of nonmyeloablative BMT, IDO activity is not. No significant differences were detectable in the kynurenine to tryptophan ratios (indicative of IDO activity) in sera of BMT recipients treated with CTLA4Ig (tolerant group) versus BMT recipients treated without CTLA4Ig (nontolerant group) versus naïve controls. In vivo inhibition of IDO immediately after BMT with CTLA4Ig or several months thereafter did not block achievement of chimerism and tolerance. Thus, IDO does not play a critical role in the induction or maintenance of chimerism and tolerance in a CTLA4Ig-based BMT model.

Induction of mixed chimerism through transplantation of CD45-congenic mobilized peripheral blood stem cells after nonmyeloablative irradiation.

Clinical translation of the mixed-chimerism approach for inducing transplantation tolerance would be facilitated if mobilized peripheral blood stem cells (mPBSCs) could be used instead of bone marrow cells (BMCs). Because the use of mPBSCs for this purpose has not been investigated in nonmyeloablative murine protocols, we explored the engraftment potential of mPBSCs in a CD45-congenic model as a first step. After 2, 1.5, or 1 Gy of total body irradiation, CD45.1 B6 hosts received unseparated granulocyte colony-stimulating factor-mobilized CD45.2 B6 PBSCs or unseparated CD45.2 B6 BMCs. The same total cell numbers, or aliquots of mPBSCs and BMCs containing similar numbers of c-kit+ cells, were transplanted both with and without a short course of rapamycin-based immunosuppression (IS). Transplantation of mPBSCs induced long-term multilineage macrochimerism, but chimerism levels were significantly lower than among recipients of the same number of BMCs. Transplanting aliquots containing similar numbers of c-kit+ cells reduced the difference between mPBSCs and BMCs, but lower levels of chimerism were nonetheless observed in mPBSC recipients. Chimerism levels correlated more closely with the number of transplanted progenitor cells as determined by colony-forming unit assays. IS did not affect chimerism levels, indicating that the donor CD45 isoform or other minor disparities do not pose a major barrier to engraftment. Our findings indicate that under nonmyeloablative conditions, progenitor cells contained in mPBSCs have an engraftment capacity similar to progenitor cells from BMCs, allowing induction of lasting mixed chimerism with moderate cell numbers. On a cell-per-cell basis, unseparated BMCs have some advantages that may be minimized if the number of progenitor cells is equalized. These results are expected to facilitate the development of mPBSC-based allogeneic tolerance protocols.

Short-term immunosuppression facilitates induction of mixed chimerism and tolerance after bone marrow transplantation without cytoreductive conditioning.

BACKGROUND: Induction of mixed chimerism and tolerance usually requires cytoreduction or transplantation of high numbers of bone marrow cells (BMC). However, such protocols have only a suboptimal success rate and, more importantly, equivalent numbers of BMC cannot be routinely obtained in the clinical setting. The authors therefore evaluated whether a short-course of immunosuppression (IS) given in addition to co-stimulation blockade would facilitate chimerism induction and allow reduction of the minimally required number of BMC without cytoreduction. METHODS: B6 mice received 200, 100, or 50 x 10 unseparated BMC from Balb/c donors plus an anti-CD40L monoclonal antibody (mAb) and CTLA4Ig (without irradiation or cytotoxic drugs). Some groups were treated additionally with IS (rapamycin, methylprednisolone, and mycophenolate mofetil for 4 weeks after bone marrow transplantation), donor-specific transfusion (DST), or anti-OX40L mAb, as indicated. RESULTS: IS led to long-term multilineage chimerism in 9 of 10 mice receiving 200 x 10 BMC (without IS, 1 of 4; P<0.05), in all mice (n=10) receiving 100 x 10 (without IS, 6 of 9; P<0.05), and notably in 9 of 10 mice treated with 50 x 10 BMC (without IS, 4 of 10; P<0.05). With transient IS, donor skin grafts were accepted longer than 170 days in 9 of 10 mice receiving 200 x 10 (without IS, 0 of 5 mice; P<0.05), all mice receiving 100 x 10 (without IS, 6 of 9; P<0.05), and 6 of 11 mice receiving 50 x 10 BMC (without IS, 4 of 10). The use of DST or anti-OX40L mAb had no beneficial effect. CONCLUSIONS: Transient IS significantly improves rates of chimerism and donor skin graft survival, and allows lasting mixed chimerism after transplantation of only 50 x 10 BMC. Thus, IS might help in the further development of noncytoreductive chimerism protocols.

The role of non-deletional tolerance mechanisms in a murine model of mixed chimerism with costimulation blockade.

Peripheral and central clonal deletion are important tolerance mechanisms in models using bone marrow transplantation (BMT) with costimulation blockade (CB). However, since tolerance can be found before peripheral deletion is complete and since elimination of recipient CD4(+) cells at the time of BMT prevents tolerance induction, we investigated the potential roles of regulation and anergy in such a murine model. We found that transient elimination of CD25(+) cells or neutralization of IL2 immediately after BMT and CB prevented the induction of skin graft tolerance. Cotransfer into SCID mice of CD4(+) cells taken from chimeras early after BMT, together with naive recipient-type CD4(+) cells significantly prolonged donor skin graft survival. In contrast, cotransfer of CD4(+) cells harvested from chimeras late after BMT did not prolong donor skin graft survival. Besides, depletion of CD25(+) cells in established chimeras several months post-BMT did not break tolerance. In vivo administration of recombinant IL2 inhibited chimerism and tolerance neither early nor late post-BMT, arguing against a decisive role for classical anergy. Thus, CD4 cell-mediated regulation contributes significantly to tolerance induction early after BMT, but appears to have no critical role in the maintenance of tolerance.

Mechanisms of tolerance induction through the transplantation of donor hematopoietic stem cells: central versus peripheral tolerance.

The transplantation of donor hematopoietic stem cells has been used successfully in numerous experimental settings to induce donor-specific tolerance. After appropriate host conditioning, hematopoietic stem-cell transplantation leads to a lasting state of donor macrochimerism that is associated with a robust form of tolerance. One of the key factors in the success of this approach is its reliance on intrathymic clonal deletion to ensure lifelong tolerization of newly developing T cells. Evidence for ongoing central deletion comes from studies following superantigen-reactive T cells and from experiments using mice transgenic for an alloreactive T-cell receptor. In protocols inducing tolerance through macrochimerism, the preexisting mature T-cell repertoire is controlled by either globally destroying all T cells before the hematopoietic cell transplantation or, in more recent models, by tolerizing it through co-stimulation blockade. The peripheral mechanisms induced by hematopoietic stem-cell transplantation and co-stimulation blockade include both extrathymic clonal deletion and the nondeletional mechanisms anergy, suppression, or both. In addition to these immunologic hurdles, a physiologic engraftment barrier has to be surmounted for the successful induction of mixed chimerism. This can be achieved by cytoreductive host treatment or by the infusion of high numbers of donor hematopoietic cells. A detailed delineation of the mechanisms responsible for tolerance induction after hematopoietic stem-cell transplantation is expected to help in the translation of these experimental protocols to clinical organ transplantation.

The influence of immunosuppressive drugs on tolerance induction through bone marrow transplantation with costimulation blockade.

We recently developed a murine protocol for the induction of allogeneic mixed chimerism and tolerance employing nonmyeloablative total body irradiation (TBI), standard-dose bone marrow transplantation (BMT), and costimulation blockade (cobl) with an anti-CD154 monoclonal antibody (mAb) plus CTLA4Ig. We now evaluated whether a short course (1 month) of immunosuppressive drugs, which would be ethically required in the clinical setting of organ transplantation to prevent graft loss in case tolerance is not achieved, interferes with tolerance induced with this regimen. Our results show that calcineurin inhibitors (cyclosporin A [CyA] or tacrolimus [FK]) inhibit development of long-term chimerism and abrogate tolerance induction in this model. Rapamycin (rapa), methylprednisolone (MP), FTY720, and mycophenolate mofetil (MMF), in contrast, have no negative effect on chimerism or tolerance development. Peripheral deletion of donor-reactive T cells, which usually occurs in the weeks following BMT in this model, is blocked by CyA and FK, but not by the other drugs tested. Furthermore, we found that the additional use of compatible immunosuppressive drugs (rapa plus MMF plus MP) allows the dose of TBI to be reduced, so that mixed chimerism and donor skin-graft acceptance can be achieved with 1 Gy using clinically feasible cell numbers. Thus, this protocol of BMT with costimulation blockade can be safely combined with a clinically tested immunosuppressive regimen to permit success with a lower dose of irradiation. These results should facilitate clinical application of this tolerance strategy.