Arvind Chhabra

Purpose: The novel coronavirus has not only caused significant illness and loss of life, it has caused major disruption at local, national and global levels. While the healthcare industry is experiencing growth during the pandemic, disruption to travel has affected medical tourism. This article considers the short-term factors affecting medical tourism and how they could be mitigated by incorporating technological advances to secure long-term growth.Design/methodology/approach: The study examines data provided by the Indian government as well as from non-government sources available in the public domain to review the impact of coronavirus disease 2019 (COVID-19) on medical tourism. The authors also examine data on technological advances in the healthcare industry that could help to reduce the impact of the pandemic.Findings: This study’s findings show that while in-person services have been seriously impacted in the short term, technological adaptation of medical services to facilitate remote medical consultation has significantly increased. This has enlarged the business opportunities available to hospitals and general practitioners, and it could be leveraged to enhance medical tourism.Originality/value: The article provides an analysis of the impact of the pandemic on medical tourism and how technology could be used to overcome short-term negative impacts and support longer-term development.

Derivation of human embryonic stem cell (hES) lines in 1998 was not only a major technological breakthrough in the field of regenerative medicine; it also triggered a passionate debate about the ethical issues associated with the utilization of human embryos for derivation of hESC lines. Successful derivation of induced pluripotent stem cell (iPS) lines from human somatic cells with defined reprogramming factors by Shinya Yamanaka`s group in 2007 was another breakthrough that generated enormous excitement and hope for the development of donor-specific personalized cell replacement therapies (CRT) without the ethical dilemma associated with it. As we approach twentieth anniversary of derivation of hESC lines and the tenth anniversary of isolation of donor-specific iPSC lines, this manuscript summarizes the key advances in pluripotent stem cell (PSC) research field that led to derivation of human iPSC lines, different methodologies for derivation iPSC lines and characterization of the mechanism of reprogramming. We will also review progress towards generating donor-specific somatic cell lineages from iPSC lines, especially the functional immune cell lineages, and progress towards advancing these findings to the clinic. Finally, we will discuss the challenges, such as genome instability and inherent immunogenicity of hPSC lines that need to be addressed to develop safe and effective iPSC-based CRT.

Donor-specific induced pluripotent stem cells (iPSC) offer opportunities for personalized cell replacement therapeutic approaches due to their unlimited self-renewal potential and ability to differentiate into different somatic cells. A significant progress has been made towards generating iPSC lines that are free of integrating viral vectors, development of xeno-free culture conditions and differentiation of pluripotent stem cells (PSC) into functional somatic cell lineages. Since donor-specific iPSC lines are genetically identical to the individual, they are expected to be immunologically matched and these iPSC lines and their cellular derivatives are not expected to be immunologically rejected. However, studies in mouse models, utilizing rejection of teratomas as a model, have claimed that syngenic iPSC lines, especially the iPSC lines derived with integrating viral vectors, could be inherently immunogenic. This manuscript reviews current understanding of inherent immunogenicity of PSC lines, especially that of the human iPSC lines and their cellular derivatives, and strategies to overcome it.

Donor-specific induced pluripotent stem cells (iPSC) can be used to generate desired cell types, including naive immune effectors, for the treatment of different diseases. However, a greater understanding of the inherent immunogenicity of human iPSC and their cellular derivatives is needed for the development of safe and effective cell-replacement therapies, given that studies in mouse models claimed that the syngenic mouse iPSC lines can be immunogenic. We report the characterization of the innate and adaptive immune mechanisms in human iPSC lines derived from peripheral blood–derived dendritic cells using a nonintegrating RNA virus, Sendai virus. We show that these iPSC lines express mRNA of TLR molecules and the Ag-presentation pathway intermediates; however, these mRNA are not translated into functional proteins, and these iPSC lines do not induce TLR-mediated inflammatory cytokine responses or inflammasome activation. We also show that these iPSC lines do not activate T cells in an allogenic MLR; however, they express low levels of MHC class I molecules that can efficiently acquire antigenic peptides from their microenvironment and present them to Ag-specific T cells. In addition, we show that these iPSC lines can be efficiently differentiated into hematopoietic stem cell precursors, as well as APC, under appropriate culture conditions. Taken together, our data show that the dedifferentiation of human dendritic cells effectively shuts down their immunogenic pathways and implicates transcriptional and posttranscriptional mechanisms in this process.

Objectives: Adoptive cancer immunotherapy (ACT) with transgenic T cell receptor (TCR) engineered (TCReng) anti-tumor T cells has produced encouraging results, however, efficacy of these approaches need improvement. Since premature activation induced cell death (AICD) of adoptively administered T cells could be a major impediment, we examined the mechanism(s) underlying AICD in TCReng CD8+ cytolytic T lymphocytes (CTL). Methods: AICD in human tumor antigen-specific MHC class I restricted TCR engineered CD8+ CTL was induced by exposing them to cognate peptide epitope. Results: We show that TCReng CD8+ human primary CTL undergo AICD even upon encountering their cognate peptide epitope for the very first time. AICD in TCReng CTL is a death-receptor-independent, JNK activation-driven intrinsic processes, in which p53-mediated mitochondria-centric, non-transcription-dependent pathway plays an essential role. Activated JNK modulates mitochondrial membrane integrity in CTL undergoing AICD by directly interacting with Bcl family protein, Bim, and the mitochondrial membrane pore complex, voltage dependent anion channel (VDAC), leading to the release of caspase-independent death executioner, apoptosis inducing factor (AIF), accumulation of single strand DNA breaks and eventually to cell death. Conclusions: Our findings offer opportunities to interfere with AICD in TCReng CD8+ anti-tumor CTL for sustaining them longer for producing better clinical outcomes.

Engaging CD4 T cells in antitumor immunity has been quite challenging, especially in an Ag-specific manner, because most human solid tumors usually do not express MHC class II molecules. We have recently shown that human CD4 T cells engineered to express a human melanoma–associated antigenic epitope, MART-127–35, specific MHC class I–restricted transgenic TCR function as polyfunctional effectors that can exhibit a helper as well as cytolytic effector function, in an epitope-specific and MHC class I–restricted manner (Chhabra et al. 2008. J. Immunol. 181: 1063–1070; Ray et al. 2010. Clin. Immunol. 136: 338–347). TCR-engineered (TCReng) CD4 T cells therefore have translational potential, and clinical trials with MHC class I TCReng CD4 T cells are under way. In this study, we show that although TCReng CD4 T cells could be useful in cancer immunotherapy, they are also susceptible to epitope-specific activation-induced cell death (AICD). We also show that the AICD in TCReng CD4 T cells is a death receptor–independent process and that JNK and p53 play critical roles in this process as pharmacological inhibitors targeting JNK activation and p-53–mediated transcription-independent mitochondria-centric death cascade rescued a significant fraction of TCReng CD4 T cells from undergoing AICD without affecting their effector function. Our data offer novel insights toward AICD in TCReng CD4 T cells and identify several potential targets to interfere with this process.