Basics Of Transplantation

Basic History

On identical twins, Joseph E. Murray, a plastic surgeon, John P. Merrill, a nephrologist, and J. Hartwell Harrison, a urologist, conducted the first successful renal transplant surgery.

Roy Calne was the pioneer in introducing Azathioprine's effectiveness in preventing rejection. One medicine called azathioprine (AZA) is used to treat and control active rheumatoid arthritis (RA) and to avoid rejection of kidney transplants. Cyclosporine was also introduced by him. A calcineurin inhibitor used as an immunosuppressive drug is cyclosporine.

The first liver transplant is performed by Thomas Starzl. He suppressed his immune system using anti-lymphocyte globulin. He also provided evidence of Tacrolimus's therapeutic effectiveness.  Richard Lillehei and William Kelly became the first people to undertake a kidney and pancreas transplant on the same human body.

The first lung transplant is performed by Fritz Derom. The first person to do a heart transplant was Christian Bernard.
David Sutherland performed the first transplant of pancreatic islet cells.

Transplant Antigens

The most significant transplant antigens are the ABO blood type and the Human Leukocyte Antigen, or HLA. Organ transplantation does not require compatibility with the Rhesus Antigen (RH). Graft rejection is thought to be most frequently caused by the HLA antigen.

The HLA protein serves as an antigen recognition unit in the body. High polymorphism exists in the HLA antigen. The reason for this is that each person's amino acid sequence is very different. The more similar and appropriate they are for one another, the less they differ.

Every HLA component is present. The three most significant HLAs in organ transplantation are A, B, and DR.  A complete match or full house at HLA loci A, B, and DR is indicated by a 000 mismatch.

Types Of Grafts

• Autograft: Autograft is the use of a tissue obtained from the same individual. It can also mean transplanting tissues into the same recipient from one side to the other. Because the transplant is taken from the same body, autografts have the advantage of low rejection rates. Additionally, the likelihood of infection is lower.
• Isograft: a transplanted organ that is genetically identical to its donor. For instance, identical twins.
• Allograft/Homograft: An allograft is a tissue that has been extracted from a donor body.  It comes from members of the same species.
• Heterograft/Xenograft: Transplanted organisms from distinct species are referred to as such.

Acute cellular rejection, acute vascular rejection, and chronic rejection are all included in the mechanism of graft rejection.One drawback of concordant xenograft is the possibility of zoonotic illness (transfer of retrovirals). Nevertheless, there is a significant chance of hyperacute rejection in the discordant xenograft method of graft rejection. New world monkeys and organs are not utilized due to physiological problems. One could think of pigs.

Types Of Allograft  Rejection

HyperAcute Rejection

Hyperacute rejection happens minutes or hours after grafting and is typically brought on by particular antibodies against the transplant.  Because of the ABO or premade anti-HLA antibody, it is regarded as the initial graft malfunction.

Interstitial hemorrhage and intravascular thrombosis are its defining features. The liver and heart are comparatively resistant to experiencing this rejection; the kidney is especially susceptible to hyperacute rejection.

Acute Rejection

Acute transplant rejection is when the immune system rejects a transplanted organ because it perceives it as foreign, which can happen days to months following a transplant.  The prognosis is uncertain and acute transplant rejection is frequent.

It may happen five days to six months from now. On the other hand, it typically appears between five days and one month.

It is mostly dependent on the infiltration of mononuclear cells and is T-cell dependent.  It may be mediated by cells, antibodies, or even both.

Steroid and immunosuppressive drug dosages can often reverse acute rejection. The BANFF criteria serve as a guide when searching for acute rejection.

HPE: Infiltrates of mononuclear matter in arteries and tubules. One recognized diagnostic indicator is the deposition of component fragments (C4d) in peritubular capillaries.

Chronic Rejection

The main reason organ transplants fail is chronic rejection. As the organ gradually loses its ability to operate, symptoms begin to show. Medication is not an effective treatment for this kind of rejection. Some individuals could require a second transplant.

It happens after six months and is the most typical reason for graft failure.  Antibodies are important here.  Pathogenesis is also influenced by non-immune elements. Myointimal growth of the graft arteries, which results in ischemia and fibrosis, is its defining feature.

The combination of acute rejection and vascular inflammation is one of the most significant risk factors for chronic rejection.

Poor HLA match, CMV infection, prolonged cold ischemia period, elevated blood lipids, and insufficient immunosuppression—which includes noncompliance—are additional risk factors linked to chronic rejection.

When chronic rejection occurs in different organs, it shows different manifestation that includes as follows:

• Kidney- Glomerular sclerosis and tubular atrophy
• Pancreas- acinar loss and islet dysfunction
• Heart-accelerated coronary artery disease
• Liver-vanishing bile duct syndrome
• Lungs- obliterative bronchiolitis 

Graft Vs Host Disease

 A systemic illness known as "graft-versus-host disease" (GvHD) develops when the recipient's bodily cells are attacked by the graft's immune cells, which regard the host as alien. The term "host" describes the tissues of the receiver, whereas "graft" refers to transplanted or donated tissue.

It is the opposite of graft rejection and mostly affects the liver, skin, and small intestine after transplantation. • In graft versus host disease, the recipient is typically attacked by lymphocytes from the donor organ.

Crossmatch Techniques

There are four types of crossmatch techniques which include the following:

Complement Dependant Lymphocytotoxicity

 Complement-dependent cytotoxicity (CDC) is an immunological reaction in which the complement cascade is activated and drawn to the targeted cell surface, lysing the target cells.  To verify complement-dependent efficacy in cancer immunotherapy, the CDC assay backs the validation of therapeutic antibodies.

The test that uses donor T or donor B cells is the least sensitive one. Only detects elevated levels of T and B cells. It is limited to identifying high levels of HLA antibodies. A positive CDC crossmatch is typically seen as an indicator against receiving a transplant from that specific donor.

Flow Cytometry Crossmatch (FXCM)

 Unlike the CDC, it usually finds minimal amounts of circulating antibodies, and the positive crossmatch is not usually linked to hyperacute rejection.

The immunological serum of the recipient, donor lymphocytes, and fluorescently labeled antibodies are combined in a sample during flow cytometry cross-matching (FXCM). • The antibodies are specific to the donor HLA and different T-cell and B-cell specific markers (e.g., CD3, 5, and 8 for T-cells, and CD19, 20, and 21 for B-cells).

Pronase, a proteolytic enzyme that eliminates non-HLA surface peptides, can be briefly incubated with donor cells to minimize false positive test findings.

Solid Phase Antigen Bead Test (SAB)

 We refer to it as a virtual crossmatch. For instance, a center might decide to reject a possible recipient if it is discovered that they have significant DSA To HLA-A2 and HLA-DR17.
This is the sole method for identifying the antigen present in the recipient's serum; the donor and recipient's serums are not combined.

Panel Reactive Antibody Assay

The PRA assay utilizes complement-fixation to evaluate if a recipient's serum can effectively lyse a panel of T-cells from a prospective donor group.  Relative to non-sensitized individuals, there is a 50% chance of being transplanted for an 80 PRA of 20%–80%, but only a 5% chance for a PRA higher than 80%.

PRA does not represent all donors; it only identifies anti-HLA I antibodies. The PRA test determines if a kidney transplant candidate's serum can lyse donor lymphocytes from a panel; a positive result carries a high risk of hyper-acute rejection and is regarded as an absolute contraindication to kidney transplantation.

The probability of a positive crossmatch is expressed as a percentage, and a high PRA indicates a higher risk of rejection, which includes surrogate markers to gauge the difficulty in locating a suitable donor and the ensuing risk of graft rejection.
Luminex technique, which uses flow cytometry—the "gold standard"—and HLA-coated luminous microbeads, is a significant advancement in anti-HLA antibody screening.

When a kidney transplant candidate has a high PRA level in their serum, this method can identify donor-specific antibodies (DSAs). Given that all organ donors are required to complete HLA typing, selecting donors who do not possess undesirable antigens (i.e., a virtual negative match) might guarantee a negative cross-match for recipients with a high PRA level.

Infection Post Transplant

Immunosuppressive medications increase the risk of infection following a transplant. These drugs lessen your body's capacity to fight infections, but they also prevent your immune system from fighting the new organ.

Less than a month: this is typically a nosocomial infection exclusive to that institution. Within the first month, bacterial infections are the most common type of infections.

One to six months: The cellular immune system regulates this infection. The fungi that cause infections most frequently are:

• The Candida
• Pneumocystis
• Aspergillus
• Cryptococcus.

The patient is prescribed clotrimazole lozenges and Nystatin suspension for one to three months in order to treat or recover from the infection.

CMV is the most prevalent type of virus. Six months after transplant, viral infection is most frequently observed in patients. The viruses that cause viral infections are polyomavirus, hepatitis virus, herpes virus, and EBV. Give Valacyclovir for three months as part of the treatment.

When there is a bacterial infection, it can involve germs such as Toxoplasmosis, Nocardia, and Listeria monocytogenes. Give clotrimazole for three months as part of your treatment.

CMV Infection

A common virus is the cytomegalovirus (CMV). Your body harbors the virus for life after infection. Since CMV seldom creates issues for healthy individuals, the majority of people are unaware that they have it.

Sexual contact and contact with bodily fluids such as tears, saliva, blood, breast milk, pee, and feces can spread CMV. Only when CMV is "active" can it be transmitted.  In clinical transplantation, it is the most significant pathogen.

It usually happens between 30 and 50 days following the transplant process. A biopsy combined with past records can be used to detect CMV infection.  IV ganciclovir is preferred for therapy.

There are some nonspecific signs and symptoms that are related to CMV infection

• Fever
• Malaria
• Arthralgia
• Thrombocytopenia
• It shows intestinal pneumonia, enterocolitis, and disseminated disease.

BK Virus

It is linked to nephropathy and is a member of the Polyomavirus family. It usually happens one to four months following transplantation.  The pathology technique in kidney transplantation uses PCR to detect it in blood and urine.

Nephropathy, widespread vasculopathy, and ureteric strictures are linked to the BK virus's urinary excretion.  Early identification and immunosuppressive drug reduction are critical components of treatment, as they lower graft loss from 90% to 10%.

> 6 months

The majority of UTIs are treated with antibiotics specific to the culture, with the exception of adenovirus and polyomavirus UTIs, which are treated by reducing immunosuppression. • The key factors influencing infection are graft function, rejection risk, and prior infection.

Post Transplant Malignancy

The Standard Incidence Ratio (SIR) indicates the likelihood of cancer following transplantation in relation to the overall population. Regarding the broader populace, the standard incidence ratio is regarded as 1.

After transplantation, Kaposi's sarcoma is thought to have a 300-fold increased risk of developing compared to a normal individual.

Standardized Incidence Ratio with >5 is for : 

• Non-Hodgkin's Lymphoma (EBV)
• Vulval ( human papillomavirus)
• Hepatocellular Carcinoma (HCV) 

Kidney, bladder, and penile cancers all have higher chances or risk factors for post-transplant malignancy.  There is a lower incidence of prostate and breast cancer among transplant patients.  Skin cancer is the most common type of malignancy after solid organ transplantation. After receiving an organ transplant, skin cancer is known as squamous cell carcinoma.

PTLD ( Post Transplant Lympho-proliferative Disorder)

Epstein-Barr virus (EBV) is linked to proliferative B-cell disorders such PTLD. It can be acquired from environmental exposure, donor exposure, or primary infection, which happens often. About 23% of patients have PTLD that is EBV-negative.

There is variation in the incidence of PTLD, primarily related to the kind of organ transplant received and the degree of immunosuppression administered.  EBV is the main cause of it.

In the event of lymphadenopathy or involvement of extra nodal locations such as tonsils, gastrointestinal system, liver, or transplanted organ, the condition resembles infectious mononucleosis more closely.

It is treatable with immunosuppressive medications.

Since thiotepa may have extra myelosuppressive effects, mitomycin should be the first line adjuvant for superficial transitional cell cancer. BCG immunotherapy should be used with caution as it carries the highest risk of systemic infection.

Hope you found this blog helpful for your NEET SS Transplantation preparation. For more informative and interesting posts like these, keep reading PrepLadder’s blogs.